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Amino acids as selective sulfonamide acylating agents
Abstract
Acylation of antimalarial and bacteriostatic sulfonamides with N-protected amino acids and peptides was carried out using standard peptide coupling methods. These acylation reactions are regioselective for the N-4 nitrogen atom of diazine-containing sulfonamides. In contrast, only N-1 coupling was found for sulfisoxazole, an isoxazole-based sulfonamide. Computational studies suggest that a combination of geometrical, thermodynamic and electronic factors are responsible for the different reactivities reported. (C) 2003 Elsevier Ltd. All rights reserved.
... The major role of DKP in prodrug design falls in the domain of approach (ii): by linking adequate dipeptide carriers to a drug, a prodrug can be created which undergoes a strictly chemical cyclization-elimination process via intramolecular aminolysis of the dipeptide moiety to a DKP, with simultaneous departure of the free parent drug (Fig. 3.1.8, Gomes, 2003). ...
... As referred in the preceding section, the aim of the present work is to clarify if accurate thermochemical data could be obtained using rather cheap computational approaches similar to those currently used to estimate gas-phase standard molar enthalpies of formation of organic molecules and small inorganic compounds. In the past few years, the B3LYP method [54,55] has been combined with both the 6-31G(d) and 6-311+G(2d,2p) basis sets [56][57][58] in the estima-tion of thermochemical data for a large variety of compounds [50][51][52][59][60][61][62][63]. In those works, the smaller basis set has been used to optimize the geometry of all compounds and to compute the vibrational frequencies at T=298.15 K and scaled by 0.98. ...
... We employ a large basis set, augmented by diffuse functions, so as to obtain accurate deprotonation and condensation energies, avoiding the pitfalls of previous theoretical studies on anionic silicates. Trends in gas-phase energies can provide useful insights about complex reactions in solution (Pereira et al., 1999a;Gomes et al., 2003;Camps et al., 2006;Ferraz et al., 2007), but cannot be quantitatively compared to experimental solution chemistry, since solvation effects are not accounted for. In an attempt to circumvent this problem, we have repeated the energy calculations in the presence of a continuum model solvent. ...
The gas-phase stabilities of linear, branched and cyclic silicates made of up to five silicon atoms were studied with density functional theory (DFT). The starting geometries for the DFT calculations at the B3LYP/6-311+G(2d,2p) level of theory were obtained from classical molecular dynamics simulations. We have observed that geometric parameters and charges are mainly affected by the degree of deprotonation. Charges on Si atoms are also influenced by their degree of substitution. The enthalpy of deprotonation of the neutral species was found to decrease with the size of the molecule, while the average deprotonation enthalpy of highly charged compounds increased with molecular size. Furthermore, the formation of rings in highly charged silicates is enthalpically preferred to chain growth. These observations result from two competing effects: the easier distribution of negative charge in silicates with low charge density and the strong intramolecular repulsions present in silicates with high charge density. As a consequence, highly charged silicates in the gas phase tend to be as small and as highly condensed as possible, which is in line with experimental observations from solution NMR. (C) 2008 Elsevier Ltd. All rights reserved.
... However, the major role of DKP in prodrug design falls in the domain of approach (ii): by linking adequate dipeptide carriers to a drug, a prodrug can be created which undergoes a strictly chemical cyclization-elimination process by intramolecular aminolysis of the dipeptide moiety to a DKP, with simultaneous departure of the free parent drug (Scheme 10) [55, 56]. In this connection, peptide derivatives of some drugs have been prepared and evaluated as prodrug candidates where prodrug activation processes involved DKP formation. ...
Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter- and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990 s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.
Herein we demonstrate a chemoselective reaction of Nβ‐protected amino alkyl sulfonyl azides with in situ generated Nα‐protected amino acid selenocarboxylates via step wise intramolecular cyclization followed by decomposition to obtain N‐acyl sulfonamide tethered peptidyl conjugates. The protocol offers the synthesis of orthogonally protected N‐acyl sulfonamide tethered peptidomimetics under simple and mild reaction conditions employing commercially available amino acids in presence of NaBH2Se3 as a selenating agent. Also, the synthesis of N‐acyl sulfonamide tethered amino acid and aryl conjugates were accomplished as an extension of the above strategy. This protocol offers an improved alternative protocol to synthesize N‐acyl sulfonamides (NAS). Orthogonally protected NAS tethered dipeptides, Nα‐protected dipeptide derived NAS, NAS tethered amino acid and aryl conjugates (acid labile tBu‐side chain protected serine and tyrosine showed tolerance under the reaction condition) and NAS derived from coumaric and thiophene acid has been explored by selenocarboxylate and sulfonyl azide coupling. All the novel N‐acyl sulfonamide molecules have been obtained in good yields.
Modelling of appropriate structures of prodrugs is aimed at numerous barriers (pharmaceutical, pharmacokinetic, pharmacodynamic), which the drug must overcome before getting to the site of action. The requirement is to achieve as high therapeutic effect as possible, without unfavourable effects, while minimizing toxicity of the drug by its controlled release at the site of action. At that the bonding to carrier (by ester or amide bonds) and the activation mechanism (enzymatic or chemical activation) are decisive. Chemical activation possesses some advantages over the enzymatic one: first of all it is not affected by biological factors, which can lead to individual differences in drug metabolism. This is why the research and number of studies of prodrugs activated by nonenzymatic mechanisms is steadily increasing. One of the used approaches is release of the drug proper by intramolecular nucleophilic cyclization of the carrier part of the prodrug molecule or release of the cyclic drug. Drug eliminations by intramolecular cyclization occur with prodrugs of the phenol, alcohol and amine types and may proceed by one-or two-step activation.
The acylation of bioactive primaquine-based imidazolidin-4-ones was studied using Nα-Boc-protected glycine as acylating agent. Two synthesis routes, eight different coupling methods and seven distinct solvents were compared. Mild carbodiimide-based couplings on high dielectric constant solvents such as DMF or MeCN increased acylation yields, whereas alcohols inhibited carbodiimide-mediated acylations to take place. Achievement of the synthetic goals was limited by the size of the imidazolidin-4-one ring substituents R1, R2 and R3, but resort to MW-assisted synthesis allowed overcoming such obstacle, though with very modest reaction yields. All reactions involving a Boc-protected amino acid were regioselective, independent of reaction conditions employed. In contrast, regioselective acetylation of the imidazolidin-4-ones could only be achieved by resort to very mild coupling procedures.
The N-acylation of sulfonamides with carboxylic acid anhydrides in the presence of Lewis acids is described. Several Lewis acids such as BF3·Et2O, ZnCl2, MoCl5, TiCl4, B(C6F5)3, Sc(OTf)3 and I2 were found to catalyze the reaction efficiently to furnish the N-acylated products in good yields under solvent-free conditions. The reactions of various sulfonamides were studied with different carboxylic acid anhydrides including the less reactive benzoic and pivalic anhydrides, in the presence of 3mol% ZnCl2 as the catalyst. Carboxylic acids were also successfully used as acylating agents via the mixed anhydride method.
New strong Lewis acid SnTf-MCM-41 and SnTf-UVM-7 catalysts with unimodal and bimodal pore systems were prepared in a two-step synthesis in which the triflic acid (Tf) was incorporated to previously synthesized mesoporous tin-containing silicas. The Sn incorporation inside the pore walls was carried out through the Atrane method. The SnTf-UVM-7 catalysts were prepared by aggregating nanometric mesoporous particles defining a hierarchic textural-type additional pore system. Following these procedures, catalysts with different Si/Sn ratios—21.8 to 50.8 for SnTf-MCM-41 and 18.4 for SnTf-UVM-7—were prepared. These new materials were tested in the acylation of aromatic sulfonamides using acetic acid as the acylating agent and in the synthesis of (dl)-[α]-tocopherol through the condensation of 2,3,6-trimethylhydroquinone (TMHQ) with isophytol (IP). The activity data indicate that these heterogeneous catalysts are very active, corresponding to high yields in acylated compounds as 65.5% and very high selectivity to (dl)-[α]-tocopherol (94%, for a conversion of 98%).
A convenient synthetic method for N-acylation of sulfonamides in the presence of P2O5/SiO2 is described. Carboxylic acid anhydrides and carboxylic acid chlorides were used as acylating agents and the reactions were carried out in CH2Cl2 or solvent- free conditions. The catalyst can be recovered by simple filtration and can be used in the subsequent reactions.
A computational study at the density functional theory level was performed on bioactive and model sulfonamides with the aim of determining the factors affecting the acidity of the sulfonamido group. The effects of introducing different substiments at either the para-aryl or the N-1-sulfonamide positions were independently analyzed. A linear correlation was found between sulfonamide acidity and the Hammett constants or charge of the SO2 group of substituents at the para-aryl position. Most N-1-substituents were taken from bacteriostatic sulfonamide structures and presented a more complex behavior, possibly due to a conjugation of steric and electronic factors. In the latter situation, sulfonamide acidity and the charge of the SO2 group were not linearly correlated. Interestingly, the acidity of the sulfonamido group was found to be correlated with the reactivity of sulfa drugs towards acylating agents. The implications for the design of suitable sulfonamide prodrugs are discussed. (C) 2005 Elsevier Ltd. All rights reserved.
The standard enthalpy of formation of the 2-amino-3-quinoxalinecarbonitrile-1,4-dioxide compound in the gas-phase was derived from the enthalpies of combustion of the crystalline solid measured by static bomb combustion calorimetry and its enthalpy of sublimation determined by Knudsen mass-loss effusion at T
= 298.15 K. This value is (383.8 ± 5.4) kJ mol−1 and was subsequently combined with the experimental gas-phase enthalpy of formation of atomic oxygen and with the computed gas-phase enthalpy of formation of 2-amino-3-quinoxalinecarbonitrile, (382.0 ± 6.3) kJ mol−1, in order to estimate the mean (N–O) bond dissociation enthalpy in the gas-phase of 2-amino-3-quinoxalinecarbonitrile-1,4-dioxide. The result obtained is (248.3 ± 8.3) kJ mol−1, which is in excellent agreement with the B3LYP/6-311+G(2d,2p)//B3LYP/6-31G(d) computed value.
A description of the ab initio quantum chemistry package GAMESS is presented. Chemical systems containing atoms through radon can be treated with wave functions ranging from the simplest closed-shell case up to a general MCSCF case, permitting calculations at the necessary level of sophistication. Emphasis is given to novel features of the program. The parallelization strategy used in the RHF, ROHF, UHF, and GVB sections of the program is described, and detailed speecup results are given. Parallel calculations can be run on ordinary workstations as well as dedicated parallel machines. © John Wiley & Sons, Inc.
Theoretical studies using ab initio molecular orbital and density functional methods have been carried out on sulfonamide HS(O)2NH2 to understand the S–N interactions present in the sulfonamide. Complete optimisation at HF/6-31+G∗, MP2/6-31+G∗ and B3LYP/6-31+G∗ levels have shown that the NH2 and SO2 units are in an eclipsed arrangement. The effect of substituent on the S–N interactions has been analysed by studying, CH3S(O)2NH2, ClS(O)2NH2 and FS(O)2NH2. Natural bond orbital analysis has been carried out to understand various interactions present in these systems. The S–N rotational barrier obtained using G2MP2 method is 6.74kcal/mol which has been found to be more due to the repulsive interactions than the anomeric interactions.
Cited By (since 1996): 6085, Export Date: 25 August 2011, Source: Scopus
We examined mutations in the dihydropteroate synthase (DHPS) genes of Pneumocystis carinii f. sp. hominis (P. carinii) strains isolated from 24 patients with P. carinii pneumonia (PCP) in Japan. DHPS mutations were identified at amino acid positions 55 and/or 57 in isolates from 6 (25.0%) of 24 patients. The underlying diseases for these six patients were human immunodeficiency virus type 1 infection (n = 4) or malignant lymphoma (n = 2). This frequency was almost the same as those reported in Denmark and the United States. None of the six patients whose isolates had DHPS mutations were recently exposed to sulfa drugs before they developed the current episode of PCP, suggesting that DHPS mutations not only are selected by the pressure of sulfa agents but may be incidentally acquired. Co-trimoxazole treatment failed more frequently in patients whose isolates had DHPS mutations than in those whose isolates had wild-type DHPS (n = 4 [100%] versus n = 2 [11.1%]; P = 0.002). Our results thus suggest that DHPS mutations may contribute to failures of co-trimoxazole treatment for PCP.
Resistance to quinoline containing drugs, particularly chloroquine (CQ), isa major impediment to the successful chemotherapy and prophylaxis of malaria. CQ-resistant parasites fail to accumulate as much drug as their sensitive counterparts and two major hypotheses have been proposed to account for this phenemenon. CQ-resistant parasites are thought to maintain lower intracellular drug levels by means of an active efflux system, similar to that found in multi-drug resistant cancer cells, despite major differences in both the genetic and biochemical manifestations of drug resistance in the two cells types. Alternatively, CQ-resistance could be linked to a defective CQ uptake mechanism, possibly an impaired acidification process in the food vacuole of the resistant parasite. These two theories are discussed in detail in the following review. The potential of pharmacological intervention to override these resistance mechanisms is also discussed.
Synopsis
Sumatriptan is a potent and selective agonist at a vascular serotonin1 (5-hydroxytryptamine1; 5-HT1) receptor subtype (similar to 5-HT1D) and is used in acute treatment of migraine and cluster headache. Following administration of sumatriptan 100mg orally, relief of migraine headache (at 2 hours) was achieved in 50 to 67% of patients compared with 10 to 31% with placebo in controlled clinical trials. In a comparative study, oral administration of sumatriptan 100mg consistently achieved significantly greater response rates than a fixed combination of ergotamine 2mg plus caffeine 200mg during 3 consecutive migraine attacks (66 vs48% for first attack). Oral sumatriptan 100mg was also more effective than aspirin 900mg plus metoclopramide 10mg orally in a similar study. In the majority of controlled clinical trials, headache relief (at 1 hour after administration) was achieved in 70 to 80% of patients with migraine receiving sumatriptan 6mg subcutaneously compared with 18 to 26% of placebo recipients
Approximately 40% of patients who initially responded to oral or subcutaneous sumatriptan experienced recurrence of their headache, usually within 24 hours, but the majority of these patients responded well to a further dose of sumatriptan.
Patients with cluster headache were treated for acute attacks with sumatriptan 6mg subcutaneously or placebo in 2 crossover trials. Headache relief was achieved within 15 minutes in 74 and 75% of patients receiving sumatriptan in these studies compared with 26 and 35%, respectively, with placebo. Patients receiving sumatriptan 12mg had a similar response rate as those receiving 6mg, but the higher dose was associated with an increased incidence of adverse events.
Based on extensive safety data pooled from controlled clinical trials, sumatriptan is generally well tolerated and most adverse events are transient. The most frequently reported adverse events following oral administration include nausea, vomiting, malaise, fatigue and dizziness. Injection site reactions (minor pain and redness of brief duration) occur in approximately 40% of patients receiving subcutaneous sumatriptan, although the incidence appears to be markedly reduced when patients self-administer the drug with an auto-injector. Chest symptoms (mainly tightness and pressure) occur in 3 to 5% of sumatriptan recipients, but have not been associated with myocardial ischaemia except in a few isolated cases. Sumatriptan is contraindicated in patients with ischaemic heart disease, angina pectoris including Prinzmetal (variant) angina, previous myocardial infarction and uncontrolled hypertension, but is not contraindicated in patients with migraine and asthma. Data from long term studies in acute treatment of migraine and cluster headache suggest that sumatriptan remains effective and well tolerated over several months.
Thus, sumatriptan rapidly relieves migraine and cluster headache attacks in the majority of patients and is well tolerated. Although the extent of its use may be tempered by relatively high acquisition costs, sumatriptan is now firmly established as a significant enhancement to the treatment options available for these disabling diseases.
Pharmacodynamic Properties
The pathogenesis of migraine, like the mechanism of action of sumatriptan, is not completely understood. However, migraine pain is thought to result from vasodilation of cerebral blood vessels, particularly those in the dura mater, and/or release of vasoactive neuropeptides from perivascular trigeminal axons in the dura mater following activation of the trigeminovascular system. Indirect evidence suggests that serotonin is implicated in the pathogenesis of migraine. A vascular 5-HT1 receptor subtype (similar to 5-HT1D) is found predominantly in cranial vasculature and mediates constriction of cephalic arteries and arteriovenous anastomoses. Autoradiographical studies demonstrated that 5-HT1D receptors are prevalent in the human brain and function as autoreceptors
Radioligand binding studies in animal brain tissue demonstrated that sumatriptan has high affinity and relative specificity for 5-HT1D receptors (along with some affinity for 5-HT1A receptors). Ergot alkaloids have strong affinity for 5-HT1D receptors, but also have a relatively high affinity for 5-HT1A, 5-HT1C, 5-HT2 α-adrenergic and dopamine2 receptors. Studies of animal and human isolated cerebral blood vessels indicate a vasoconstrictor effect of sumatriptan, thought to be mediated by vascular 5-HT1 receptors. Sumatriptan administration in humans was associated with increased blood flow velocity in large cerebral conductance vessels, probably due to sumatriptan-induced vasoconstriction. In animal isolated tissue studies, sumatriptan had essentially no activity at 5-HT1 receptors mediating vascular smooth muscle relaxation, but weak vasoconstrictor activity mediated by vascular 5-HT1 receptors was noted in human isolated coronary arteries. Sumatriptan also had no activity at 5-HT2 or 5-HT3 receptors in animal isolated tissue studies.
Data from animal studies suggest that sumatriptan blocks neurogenic plasma extravasation, presumably by stimulating a presynaptic 5-HT1D autoreceptor, thus preventing release of inflammatory mediators within the trigeminovascular system. In humans, elevation of plasma levels of a vasoactive neuropeptide (calcitonin gene-related peptide) detected during migraine headache was attenuated by sumatriptan.
Thus, sumatriptan is a potent and selective vascular 5-HT1 receptor agonist which mediates constriction of certain large cranial blood vessels and/or inhibits release of vasoactive neuropeptides from perivascular trigeminal axons in the dura mater during a migraine attack.
Pharmacokinetic Properties
A mean plasma concentration (Cmax) of 72 μg/L was achieved after a median of 10 minutes following subcutaneaous administration of sumatriptan 6mg to healthy volunteers. Sumatriptan 100mg orally achieved a Cmax of 54 μg/L after a median of 1.5 hours; however, 80% of Cmax was achieved within 45 minutes of oral administration. Mean bioavailability of sumatriptan was 96% after subcutaneous administration and 14% after oral administration
Following parenteral administration of sumatriptan in humans, mean volume of distribution was calculated as 170L. In vitro plasma protein binding of sumatriptan ranged from 14 to 21%. Animal data indicate that sumatriptan poorly penetrates the blood-brain barrier.
Sumatriptan is extensively metabolised, primarily to an inactive indoleacetic acid analogue. Metabolites and unchanged drug are eliminated in the urine and faeces; urinary excretion is higher following subcutaneous than oral administration. Sumatriptan undergoes active renal tubular secretion, as indicated by a renal clearance rate of 15.6 L/h following oral administration, although renal clearance accounts for only 20% of total clearance. Mean elimination half-life is approximately 2 hours following single-dose administration of oral or subcutaneous sumatriptan. Co-administration of food or various antimigraine agents, or the presence of a migraine attack do not appear to significantly affect the pharmacokinetic profile of sumatriptan.
Therapeutic Efficacy
A number of large, double-blind clinical trials have demonstrated that sumatriptan is clearly superior to placebo in acute treatment of migraine headache. Sumatriptan 100mg administered orally achieved headache relief (i.e. reduction in headache severity) at 2 hours after administration in 50 to 67% of patients compared with 10 to 31% with placebo. Comparative studies showed that orally administered sumatriptan 100mg achieved significantly greater response rates than ergotamine 2mg plus caffeine 200mg orally for 3 consecutive migraine attacks (66 vs 48% for first attack), and response rates were higher with sumatriptan than aspirin 900mg plus metoclopramide 10mg orally. In the latter trial, statistically significant differences were noted for only the second and third attacks (56 vs 45% for first attack). In the majority of controlled studies, 70 to 80% of patients receiving sumatriptan 6mg subcutaneously experienced relief of migraine headache at 1 hour after administration compared with 18 to 26% of placebo recipients. Concurrent administration of oral dihydroergotamine as prophylactic antimigraine therapy did not appear to affect clinical response to acute treatment with subcutaneous sumatriptan. Subcutaneous administration of sumatriptan 6mg was also effective in relieving early morning migraine attacks and menstruation- associated migraine headaches, both of which are often resistant to antimigraine treatment
Patients receiving oral or subcutaneous sumatriptan in controlled clinical trials consistently required less rescue medication for unresolved symptoms than those receiving either placebo or comparator agents. Sumatriptan was also effective at relieving associated symptoms of migraine such as nausea, vomiting and photophobia/phonophobia. Sumatriptan was equally effective regardless of migraine type (with or without aura), or whether administered early (< 4 hours) or late (> 4 hours) after the onset of migraine symptoms. In clinical trials, approximately 40% of patients who initially responded to sumatriptan developed recurrence of their headache, but the majority of these patients responded to a further dose of sumatriptan.
Efficacy of subcutaneous sumatriptan 6mg in acute treatment of cluster headache was demonstrated in 2 crossover studies. Sumatriptan provided headache relief within 15 minutes of administration in 74 and 75% of patients in these trials compared with 26 and 35%, respectively, with placebo. In addition, the need for oxygen rescue therapy was reduced, functional disability was improved and the incidence of conjunctival injections was decreased with sumatriptan.
Tolerability
Pooled data from controlled studies of patients receiving sumatriptan for acute treatment of migraine indicate that sumatriptan is generally well tolerated. The most frequently reported adverse events with oral sumatriptan include nausea, vomiting, malaise, fatigue, dizziness and vertigo, which usually occur within 60 minutes of administration and are short-lived. Subcutaneous administration of sumatriptan produces minor injection site reactions in approximately 40% of patients. These are also transient and appear to be less likely when the drug is self-administered using an auto-injector. The overall incidence of serious adverse events thought to be associated with sumatriptan is 0.14%. Chest tightness and pressure occurs in 3 to 5% of patients with migraine receiving sumatriptan, but has only been associated with myocardial ischaemia in a few isolated cases. Sumatriptan is contraindicated in patients with ischaemic heart disease, angina pectoris including Prinzmetal (variant) angina, previous myocardial infarction and uncontrolled hypertension. Patients with migraine and asthma are not at increased risk of adverse events with sumatriptan, and the drug is not contraindicated in asthmatic patients. The incidence and pattern of adverse events associated with sumatriptan use does not appear to be altered by long term administration of the drug
Dosage and Administration
The recommended dose of oral sumatriptan is 100mg at the onset of migraine symptoms. If headache recurs after initial relief of symptoms, up to 2 additional 100mg doses may be taken during a 24-hour period. The maximum oral dosage is 300mg in 24 hours. The recommended dose for subcutaneous sumatriptan is 6mg at the onset of migraine or cluster headache. If symptoms recur, a second 6mg dose may be administered at least 1 hour after the first dose. The maximum subcutaneous dosage is 12mg in 24 hours
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) has been applied as coupling reagent to solid phase peptide synthesis. Furthermore, a general synthetic procedure for new derivatives of different N-hydroxy compounds has been developed. They either act as excellent activating reagents causing low racemization during condensation of peptide segments or are useful tools for the formation of active esters suitable for couplings in mixed aqueous / organic media, respectively.
Tertiary N-acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides were synthesised and evaluated as novel classes of potential prodrugs of agents containing a secondary sulfonamide group. The chemical and plasma hydrolyses of the title compounds were studied by HPLC. Tertiary N-acyloxymethylsulfonamides are slowly and quantitatively hydrolysed to the parent sulfonamide in pH 7.4 phosphate buffer, with half-lives ranging from 20 h, for 7d, to 30 days, for 7g. Quantitative formation of the parent sulfonamide also occurs in human plasma, the half-lives being within 0.2–2.0 min for some substrates. The rapid rate of hydrolysis can be ascribed to plasma cholinesterase, as indicated by the complete inhibition observed at [eserine]=0.10 mM. These results suggest that tertiary N-acyloxymethylsulfonamides are potentially useful prodrugs for agents containing a secondary sulfonamide group, especially with pKa
With the assistance of two new associate editors, Alfred G. Gilman and George B. Koelle, the fifth edition retains the excellence set by previous editions of this classic text. To maintain the same overall length, several outmoded areas have been abbreviated or eliminated. There are discussions of many new drugs, as well as promising drugs whose availability in the United States is probable in the near future.The section on chemotherapy of neoplastic diseases has undergone extensive revision. The introductory section contains a very readable and informative discussion of pharmacokinetics, pharmacodynamics, and an interesting account of the process of development and approval of new drugs. The section on Parkinson disease has been extensively revised, with major emphasis on levodopa. The chapter on neurohumoral transmission and the autonomic nervous system remains the best source of information in this complex and rapidly changing area. The treatment of diuretics is completely up to
The cyclization of H-Ala-Pro-NH2 to the 2,5-dioxopiperazine (DKP) has been studied as a model for the spontaneous cleavage of the peptide bond with concomitant formation of 2,5-dioxopiperazine that can occur at the N-terminus of a polypeptide chain. The reaction involves pre-equilibrium attack of the N-terminal amino group on the carbonyl carbon of the second residue giving a zwitterionic cyclic intermediate, T+/-, which is in acid-base equilibrium with various forms characterized by different grades of protonation, T-0, T+ and T-. The Bronsted plot for the base-catalysis and the pH-rate profile give pK(a) similar to 7 and similar to 13 for the equilibria T- + H+ reversible arrow T+/- and T- + H+ reversible arrow T-0, respectively. The reaction is subject to general base and general acid catalysis, acting on different steps. Departure of the amino group from T-0 and T- by two parallel routes gives the product. The bifunctional acid catalyst HCO3- strongly increases the reaction rate and at high concentrations causes a change of the rate-limiting step. At high pH, the overall reaction rate is limited by the trans --> cis isomerization of the Ala-Pro peptide bond.
Durch Anwendung mehrerer gaschromatographischer Racemisierungstests wurde gefunden, daß bei der DCCD-Methode1) aus einer Reihe von N-Hydroxyverbindungen als Zusatz zum DCCD das 3-Hydroxy-4-oxo-3.4-dihydro-1.2.3-benzotriazin die Racemisierung am wirkungsvollsten senkt. Auch eine racemisierungsfreie Voraktivierung ist mit dieser Verbindung möglich. Bei der Herstellung von N-Acyl-peptid-[N-hydroxy-succinimidestern] nach der DCCD-Methode wirkt sich ein Zusatz schwacher tert. Basen günstig auf Ausbeute und Racemisierung aus.
Racemization in Peptide Syntheses
Various gaschromatographic racemization tests indicate, that 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine as additive to DCCD decreases racemization in the DCCD-method to a minimum, compared with a series of N-hydroxy-compounds. It is also possible to prepare the intermediate activated esters without racemization. Addition of weak tertiary bases has a favourable effect on the yield and racemization in the preparation of N-acylpeptide-N-hydroxysuccinimide esters by the DCCD-method.
Density functional theory has been used to investigate gas-phase thermodynamic properties of phenol and dichlorophenols. Molecular geometries, energies, and vibrational frequencies were computed at the B3LYP and BP86 levels of theory. At T = 298.15 K, calculated standard enthalpies of formation are in excellent agreement with experimental data. The average deviation between calculated and experimental values is of about 2.3 kJ/mol, and in some cases, theoretical values fall within experimental uncertainty. Other proper-ties for which only a few experimental results were available in the literature were also calculated, namely, O-H homolytic bond dissociation energies, gas-phase acidities, ionization energies, and proton and electron affinities.
Several derivatives of model sulfonamides were prepared and evaluated as potential prodrug forms for the sulfonamide group occurring in several drugs such as diuretics and carbonic anhydrase inhibitors. The derivatives studied included N-acyl and N-alkoxycarbonyl derivatives, N-sulfonylamidines, sulfonylureas, an N-sulfonyl sulfilimine and an N- sulfonyl sulfoximine. The stability characteristics of the derivatives was examined in aqueous solution at various pH values as well as in the presence of human plasma and rat liver homogenate. The results obtained showed that N-sulfonylamidines and sulfonylureas are too stable to be considered as potentially useful prodrug forms. N-Acyl and N-alkoxycarbonyl derivatives of primary sulfonamides also proved very resistant to undergo chemical or enzymatic hydrolysis whereas N-acyl derivatives of secondary sulfonamides are easily hydrolyze enzymatically. Since N-alkylated sulfonamides are known to undergo dealkylation in vivo a promising prodrug approach for a primary sulfonamide involving both N-alkylation and N-acylation was suggested. N-Sulfonyl sulfilimes may also represent a potentially useful prodrug type for the sulfonamide group as assessed on the basis of the hydrolytic and enzymatic lability observed for N-p-toluenesulfonyl dimethylsulfilimine.
Scaling factors for obtaining fundamental vibrational frequencies, low-frequency vibrations, zero-point vibrational energies (ZPVE), and thermal contributions to enthalpy and entropy from harmonic frequencies determined at 19 levels of theory have been derived through a least-squares approach. Semiempirical methods (AM1 and PM3), conventional uncorrelated and correlated ab initio molecular orbital procedures [Hartree?Fock (HF), M?ller?Plesset (MP2), and quadratic configuration interaction including single and double substitutions (QCISD)], and several variants of density functional theory (DFT:? B-LYP, B-P86, B3-LYP, B3-P86, and B3-PW91) have been examined in conjunction with the 3-21G, 6-31G(d), 6-31+G(d), 6-31G(d,p), 6-311G(d,p), and 6-311G(df,p) basis sets. The scaling factors for the theoretical harmonic vibrational frequencies were determined by a comparison with the corresponding experimental fundamentals utilizing a total of 1066 individual vibrations. Scaling factors suitable for low-frequency vibrations were obtained from least-squares fits of inverse frequencies. ZPVE scaling factors were obtained from a comparison of the computed ZPVEs (derived from theoretically determined harmonic vibrational frequencies) with ZPVEs determined from experimental harmonic frequencies and anharmonicity corrections for a set of 39 molecules. Finally, scaling factors for theoretical frequencies that are applicable for the computation of thermal contributions to enthalpy and entropy have been derived. A complete set of recommended scale factors is presented. The most successful procedures overall are B3-PW91/6-31G(d), B3-LYP/6-31G(d), and HF/6-31G(d).
Despite the remarkable thermochemical accuracy of Kohn–Sham density-functional theories with gradient corrections for exchange-correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact-exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange-correlation functional containing local-spin-density, gradient, and exact-exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first- and second-row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
Incluye bibliografía e índice
The hydrolysis kinetics of a series of N-Mannich bases of carboxamides, thioamides, and other NH-acidic compounds were studied to assess their suitability as prodrugs for various drugs. The pH-rate profiles for the compounds were determined at 37 degrees and were accounted for by assuming the spontaneous decomposition of both free and protonated Mannich bases. The reaction rate for the free base increased sharply with increasing steric effects of the amine component of the N-Mannich bases and also with increasing acidity of the amide component. N-Mannich bases may be potentially useful prodrugs for NH-acidic compounds such as various amides, and ureides and for amines.
N-(Substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)carbamates based on masked active benzoxazolones (model A) and oxazolidinones (model B), respectively, were synthesized and evaluated as potential drug delivery systems. A series of alkyl and aryl N-(5-chloro-2-hydroxyphenyl)carbamates 1 related to model A was prepared. These are open drugs of the skeletal muscle relaxant chlorzoxazone. The corresponding 4-acetamidophenyl ester named chlorzacetamol is a mutual prodrug of chlorzoxazone and acetaminophen. Chlorzacetamol and two other mutual prodrugs of active benzoxazolones and acetaminophen were obtained in a two-step process via condensation of 4-acetamidophenyl 1,2,2,2-tetrachloroethyl carbonate with the appropriate anilines. Based on model B, two mutual prodrugs of acetaminophen and active oxazolidinones (metaxalone and mephenoxalone) were similarly obtained using the appropriate amines. All the carbamate prodrugs prepared were found to release the parent drugs in aqueous (pH 6-11) and plasma (pH 7.4) media. The detailed mechanistic study of prodrugs 1 carried out in aqueous medium at 37 degrees C shows a change in the Brönsted-type relationship log t1/2 vs pKa of the leaving groups ROH: log t1/2 = 0.46pKa-3.55 for aryl and trihalogenoethyl esters and log t1/2 = 1.46pKa-16.03 for alkyl esters. This change is consistent with a cyclization mechanism involving a change in the rate-limiting step from formation of a cyclic tetrahedral intermediate (step k1) to departure of the leaving group ROH (step k2) when the leaving group ability decreases. This mechanism occurs for all the prodrugs related to model A. Regeneration of the parent drugs from mutual prodrugs related to model B takes place by means of a rate-limiting elimination-addition reaction (E1cB mechanism). This affords acetaminophen and the corresponding 2-hydroxypropyl isocyanate intermediates which cyclize at any pH to the corresponding oxazolidinone drugs. As opposed to model A, the rates of hydrolysis of mutual prodrugs of model B clearly exhibit a catalytic role of the plasma. It is concluded from the plasma studies that the carbamate substrates can be enzymatically transformed into potent electrophiles, i.e., isocyanates. In the case of the present study, the prodrugs are 2-hydroxycarbamates for which the propinquity of the hydroxyl residue and the isocyanate group enforces a cyclization reaction. This mechanistic particularity precludes their potential toxicity in terms of potent electrophiles capable of modifying critical macromolecules.
We identified 40 patients (25 men and 15 women) who developed calculi composed totally or partially of sulfonamides (acetylsulfamethoxazole, sulfadiazine, and acetylsulfisoxazole) between 1980 and 1987. The incidence of sulfonamide stones is less than 1% of stones. Patient characteristics were determined from questionnaires sent to the patients and attending physicians. The majority of patients developed symptoms 1 to 4 weeks after beginning sulfonamide therapy. The bladder was the most common stone location. Obstruction of the urinary system by the acetyl derivatives of the drug is the most serious consequence of sulfonamide therapy. Early recognition of drug-related stones is essential to protect patients from recurrences, reduce the risk of renal complications, and avoid continuing ineffective therapeutic regimens.
The N4-acetyl derivatives of sulfaquinoxaline and sulfadimethoxine were stable in fortified chicken liver and thigh muscle tissues during frozen storage for 1 year at -20 and -70 degrees C. In contrast, the parent compounds depleted approximately 35% in liver tissues at -20 degrees C. The transformation of the depleted sulfa drugs to their N4-glucopyranosyl derivatives was negligible, suggesting that products other than glucosides resulted during the storage period.
Resistance to quinoline containing drugs, particularly chloroquine (CQ), is a major impediment to the successful chemotherapy and prophylaxis of malaria. CQ-resistant parasites fail to accumulate as much drug as their sensitive counterparts and two major hypotheses have been proposed to account for this phenomenon. CQ-resistant parasites are thought to maintain lower intracellular drug levels by means of an active efflux system, similar to that found in multi-drug resistant cancer cells, despite major differences in both the genetic and biochemical manifestations of drug resistance in the two cell types. Alternatively, CQ-resistance could be linked to a defective CQ uptake mechanism, possibly an impaired acidification process in the food vacuole of the resistant parasite. These two theories are discussed in detail in the following review. The potential of pharmacological intervention to override these resistance mechanisms is also discussed.
Most available nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both the constitutive cyclooxygenase-1 (COX-1) and the inducible cyclooxygenase-2 (COX-2), resulting in inhibition of prostaglandin (PG) and thromboxane (TX) biosynthesis. The inhibition of COX-2 might be the cause of the favourable anti-inflammatory, analgesic and antipyretic effects of NSAIDs, whereas that of COX-1 might result in unwanted gastrointestinal, renal and possibly other side-effects. Nimesulide is a sulfonanilide compound with anti-inflammatory properties. Its pharmacological profile (better inhibition of PG synthesis in inflammatory areas than in gastric mucosa), suggested that it might be a selective inhibitor of COX-2. In several in vitro assays using either purified COX-2 and COX-1 preparations or cell preparations (both from animal and human origins) expressing COX-1 or COX-2, ten out of eleven different groups have demonstrated that nimesulide selectively inhibits COX-2. The COX-2/ COX-1 inhibitory ratio varies, according to the assay preparation, from about 0.76 to 0.0004 i.e. a 1.3 to 2,512-fold higher selectivity for COX-2 than for COX-1. Moreover, an in vivo whole blood assay performed on healthy volunteers demonstrated a significant fall in COX-2 PGE2 production without any effect on COX-1 TXB2 production in subjects treated with nimesulide (100 mg b.i.d. for 2 weeks) versus no effect on COX-2 PGE2 and an almost total suppression of COX-1 TXB2 in subjects treated with aspirin (300 mg t.i.d. for 2 weeks). Nimesulide can thus be considered a relatively selective COX-2 inhibitor. At the recommended dosage of 100 mg b.i.d., it is as effective an analgesic and anti-inflammatory agent as classical NSAIDs, and a well-tolerated drug with few side-effects according to large-scale open studies and a global evaluation of a large number of controlled and non-controlled comparative trials.
Current gradient-corrected density-functional approximations for the exchange energies of atomic and molecular systems fail to reproduce the correct 1/r asymptotic behavior of the exchange-energy density. Here we report a gradient-corrected exchange-energy functional with the proper asymptotic limit. Our functional, containing only one parameter, fits the exact Hartree-Fock exchange energies of a wide variety of atomic systems with remarkable accuracy, surpassing the performance of previous functionals containing two parameters or more.
A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.
The orally administered acetazolamide has a limited use in glaucoma due to the systemic side effects associated with its use. It has been reported to show little effect on the intraocular pressure (IOP) of human and rabbit eyes upon topical application, probably owing to its poor bioavailability and instability at pH >5.0. In order to enhance the bioavailability of the drug, contact time between the drug molecules and the ocular surface was increased using high viscosity, water soluble polymers (PVA, HPMC), and by incorporating acetazolamide into an in situ-forming ophthalmic drug delivery system. Moreover, a penetration enhancer (EDTA) was also used in these formulations to increase the extent of absorption of the drug. Acetazolamide at a concentration of 10% was used and the formulations (eyedrop suspensions) were evaluated for their in vitro release pattern. The effect of these formulations on the IOP in normotensive conscious rabbits was also investigated. These formulations were found to be therapeutically effective with a peak effect at 2 h. A fall in IOP of up to 46.4% was observed with repeated administration of one of the formulation containing PVA, EDTA and Tween 80 (MK-5). Results indicated that a topical effect of acetazolamide can be observed if the formulation, (a) contains a suitable polymer-to increase the residence time; (b) a penetration enhancer-as acetazolamide has a low permeability coefficient i.e. 4. 1x10(-6) cm/s [Duffel, M.W., Ing. I.S., Segarra, T.M., Dixson, J.A., Barfknecht, C.F., Schoenwald, R.D., 1986. J. Med. Chem. 29, 1488-1494]; and (c) pH of the formulation is maintained at the point of maximum stability (pH< or =5.0).
New total syntheses of didemnin A and of dehydrodidemnin B are described. The latter didemnin has the highest antiproliferative activity of all members of this family of macrocyclic depsipeptides. It was produced on coupling the side chain Pyr-Pro-OH to didemnin A, which was itself synthesized by two novel routes. One of these was based on the elaboration of a linear heptadepsipeptide incorporating the first amino acid of the didemnin side chain, (R)-N(Me)-Leu. Deprotection of the amino and carboxyl terminii of this linear precursor followed by macrocyclization gave a protected derivative of didemnin A. The second route involved synthesis of the Boc-protected didemnin macrocycle from a linear hexadepsipeptide lacking (R)-N(Me)-Leu. Removal of the Boc group from the macrocycle followed by its coupling with Boc-(R)-N(Me)-Leu-OH then gave Boc-didemnin A. The overall yield was much higher for the second strategy (27% compared to 4% for the first synthesis), but both allowed synthetic didemnin A, identical with a natural sample, to be prepared. Extensive use was made of phosphonium and uronium salt-based coupling reagents, such as BOP, PyBrOP, PyAOP, HBTU, and HATU for the formation of both the secondary and tertiary amide bonds present in these complex depsipeptides.
A Textbook of Drug Design and Development
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In Biorreversible Carriers in Drug Design Theory and Application
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The synthesis was performed as described for 5c fractions containing pure product were pooled and evaporated to dryness, yielding a yellowish solid (52%) with mp 125
2.15. N 4 -BocPheGlySulfamethoxypyridazine (8c). The
synthesis was performed as described for 5c, using
BocPheGlyOH as acylating agent; the crude mixture was
eluted on a silica-gel column, using DCM/Acetone 4:1
(v/v); fractions containing pure product were pooled and
evaporated to dryness, yielding a yellowish solid (52%)
with mp 125 –1288C. d H (DMSO-d 6 ), 10.21 (s, 1H), 8.37 (t,
J¼5.5 Hz, 1H), 7.78 (d, J¼9.0 Hz, 2H), 7.72 (d, J¼9.0 Hz,
2H), 7.71 (d, J¼9.9 Hz, 1H), 7.34 (d, J¼9.9 Hz, 1H), 7.20
(m, 5H), 7.02 (d, J¼8.3 Hz, 1H), 4.20 (m, 1H), 3.92 (d,
J¼5.1 Hz, 2H), 3.81 (s, 3H), 3.05 (dd, J¼3.8, 13.7 Hz, 3H),
2.74 (dd, J¼11.0, 14.0 Hz, 1H), 1.26 (s, 9H); d C (DMSOd 6 ), 172.4, 168.3, 155.5, 153.0, 142.0, 138.2, 129.3, 128.1,
127.5, 126.3, 118.8, 78.3, 55.9, 54.6, 42.9, 37.4, 28.2. m/z
(584.65): 585.72 (MH þ ).
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35 (s, 9H); d C (DMSO-d 6 ), 173
- Hz
Hz, 2H), 3.81 (s, 3H), 1.35 (s, 9H); d C (DMSO-d 6 ),
173.4, 168.3, 155.4, 152.9, 141.9, 127.4, 126.2, 118.8, 78.3,
54.5, 49.9, 42.8, 28.2, 17.9. m/z (508.55): 508.98 (MH þ ).
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