Mino R. Caira

University of Cape Town, Kaapstad, Western Cape, South Africa

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Publications (259)503.72 Total impact

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    ABSTRACT: The interaction between the potent anticancer agent 2-methoxyestradiol (2ME) and a series of cyclodextrins (CDs) was investigated in the solid state using thermal analysis and X-ray diffraction, while the possibility of enhancing its poor aqueous solubility with CDs was probed by means of equilibrium solubility and dissolution rate measurements. Single crystal X-ray diffraction studies of the inclusion complexes between 2ME and the derivatised cyclodextrins heptakis(2,6-di-O-methyl)-β-CD (DIMEB) and heptakis(2,3,6-tri-O-methyl)-β-CD (TRIMEB) revealed for the first time the nature of the encapsulation of a bioactive steroid by representative CD host molecules. Inclusion complexation invariably involves insertion of the D-ring of 2ME from the secondary side of each CD molecule, with the 17-OH group generally hydrogen bonding to a host glycosidic oxygen atom within the CD cavity, while the A-ring and part of the B-ring of 2ME protrude from the secondary side. In the case of the TRIMEB·2ME complex, there is evidence that complexation proceeds with mutual conformational adaptation of host and guest molecules. The aqueous solubility of 2ME was significantly enhanced by CDs, with DIMEB, TRIMEB, randomly methylated β-CD and hydroxypropyl-β-CD being the most effective hosts. The 2:1 host-guest β-CD inclusion complex, prepared by two methods, yielded very rapid dissolution in water at 37 °C relative to untreated 2ME, attaining complete dissolution within 15 minutes (co-precipitated complex) and 45 minutes (complex from kneading).
    Full-text · Article · Dec 2015 · Beilstein Journal of Organic Chemistry
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    ABSTRACT: (1)H NMR-based kinetic studies have revealed the latent mechanistic complexity of deceptively simple hydrochloric acid-catalyzed reactions of salicylaldehyde-derived Baylis-Hillman adducts. Reactions conducted at 0 °C afforded 2-(chloromethyl)cinnamic acid derivatives as the major products and the corresponding 3-(chloromethyl)coumarin derivatives as the minor products. In reactions conducted in refluxing acetic acid, however, the 3-(chloromethyl)coumarin derivatives are the sole products. Variable-temperature (1)H NMR analysis permitted the determination of the rate constants and kinetic parameters involved in the pseudo-first-order formation of (Z)-2-(chloromethyl)-3-(2-hydroxyphenyl)-2-propenoic acid. The kinetic data clearly preclude the operation of classical kinetic versus thermodynamic control and indicate the operation of three independent reaction pathways. Theoretical studies of these pathways undertaken at the B3LYP/6-31G(d) level permitted rationalization of the experimental data and provided insights into the possible mechanism of the enzymic E-Z isomerization and cyclization of (E)-cinnamic acid analogues to afford coumarins.
    No preview · Article · Dec 2015 · The Journal of Organic Chemistry
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    ABSTRACT: 1,3-Dipolar cycloaddition reaction of sydnone-N-ylides, as model bis(1,3-dipoles), with acetylenic dipolarophiles in 1,2-epoxybutane under reflux gave exclusively pyrroloazines containing a sydnone moiety that resulted by preferred reaction of the N-ylide 1,3-dipole with the acetylenic dipolarophiles. The assembled sydnone-ylide hybrid structures were generated in situ from N-heteroaromatic bromides. The structure of the new compounds was assigned by IR and NMR spectroscopy and confirmed by X-ray analysis for a representative compound.
    No preview · Article · Oct 2015 · Tetrahedron
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    ABSTRACT: The three possible structural isomers of 4-(pyridyl)pyrimidine were employed for the synthesis of new pyrrolo[1,2-c]pyrimidines and new indolizines, by 1,3-dipolar cycloaddition reaction of their corresponding N-ylides generated in situ from their corresponding cycloimmonium bromides. In the case of 4-(3-pyridyl)pyrimidine and 4-(4-pyridyl)pyrimidine the quaternization reactions occur as expected at the pyridine nitrogen atom leading to pyridinium bromides and consequently to new indolizines via the corresponding pyridinium N-ylides. However, in the case of 4-(2-pyridyl)pyrimidine the steric hindrance directs the reaction to the pyrimidinium N-ylides and, subsequently, to the formation of the pyrrolo[1,2-c]pyrimidines. The new pyrrolo[1,2-c]pyrimidines and the new indolizines were structurally characterized through NMR spectroscopy. The X-ray structures of two of the starting materials, 4-(2-pyridyl)pyrimidine and 4-(4-pyridyl)pyrimidine, are also reported.
    Full-text · Article · Jun 2015 · Beilstein Journal of Organic Chemistry
  • Mino R Caira · Susan A Bourne · Halima Samsodien
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    ABSTRACT: The aim of the study was to generate alternative solid forms of 2-methoxyestradiol (2ME) and its sulfamoylated derivative 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2MES), both of which are potent anticancer agents with no significant history of solid-state investigation. Screening for polymorphs and solvates by a variety of procedures yielded four distinct species: a crystalline form of 2ME, an amorphous form of 2ME, a chloroform solvate 2ME·(CHCl3 )2 , and the hemihydrate of the bis-sulfamate, 2MES·(H2 O)0.5 . Hydrogen-bonded assembly of 2ME molecules into layers in both crystalline 2ME and its chloroform solvate was established using single-crystal X-ray diffraction. This technique also revealed disorder of the sulfamate group at position 17 in both molecules comprising the asymmetric unit in the crystal of 2MES·(H2 O)0.5 . The thermal stabilities of the crystalline phases were recorded using hot-stage microscopy, thermogravimetry, and differential scanning calorimetry, and the results were reconciled with the crystal structures. Aqueous dissolution rates measured at 37°C generally decreased in the order 2MES·(H2 O)0.5 > 2ME(amorphous) > 2ME(crystalline). © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
    No preview · Article · Jun 2015 · Journal of Pharmaceutical Sciences
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    ABSTRACT: (+)-(2R,3R)-1,1,4,4-Tetraphenylbutane-1,2,3,4-tetraol (TETROL) functions as a highly efficient host for the inclusion of cyclohexanone and 2-, 3-, and 4-methylcyclohexanone, all with 1:1 host/guest ratios. Most extraordinarily, the 3- and 4-methyl isomers are uniquely included in their higher energy axial methyl conformations rather than as their more energetically favorable equatorial analogues. In contrast, 2-methylcyclohexanone is included more conventionally in the equatorial methyl conformation. During recrystallization of TETROL from racemic 2- and 3-methylcyclohexanone, some preference is shown by the host for the (R)-enantiomer. In the latter case, this is attributed to a much stronger H-bond between a hydroxyl group of TETROL and the carbonyl group of the (R)-enantiomer (O···O 2.621(2) Å) compared with a significantly weaker H-bond to the (S)-enantiomer (3.125(8) Å). In the former instance, hydrogen-bond strengths to both enantiomers are similar, but the (R)-enantiomer engages in three (guest)CH···π(host) and three (guest)H···Car(host) contacts, whereas fewer interactions of these types are observed for the (S)-enantiomer. Calculations of geometries of the guest cyclohexanones were determined at the MP2/6-311++G(2df,2p) level and compared with those obtained at the G3(MP2) level. Finally, an interesting correlation between crystal packing indices for the three methylcyclohexanone clathrates and their respective desolvation onset temperatures was identified.
    No preview · Article · Jun 2015 · The Journal of Organic Chemistry
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    ABSTRACT: The phytoalexin trans-resveratrol, 5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol, is a well-known, potent antioxidant having a variety of possible biomedical applications. However, its adverse physicochemical properties (low stability, poor aqueous solubility) limit such applications and its inclusion in cyclodextrins (CDs) has potential for addressing these shortcomings. Here, various methods of the attempted synthesis of inclusion complexes between trans-resveratrol and three methylated cyclodextrins (permethylated α-CD, permethylated β-CD and 2,6-dimethylated β-CD) are described. Isolation of the corresponding crystalline 1:1 inclusion compounds enabled their full structure determination by X-ray analysis for the first time, revealing a variety of guest inclusion modes and unique supramolecular crystal packing motifs. The three crystalline inclusion complexes were also fully characterized by thermal analysis (hot stage microscopy, thermogravimetric analysis and differential scanning calorimetry). To complement the solid-state data, phase-solubility studies were conducted using a series of CDs (native and variously derivatised) to establish their effect on the aqueous solubility of trans-resveratrol and to estimate association constants for complex formation.
    Preview · Article · Dec 2014 · Beilstein Journal of Organic Chemistry
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    ABSTRACT: 7,8,9,10-Tetrahydropyrrolo[2,1-a]isoquinolines were obtained by 1,3-dipolar cycloaddition reactions of their corresponding N-ylides with olefinic (acrylonitrile) and symmetrical or non-symmetrical acetylenic dipolarophiles (methyl/ethyl propiolate, dimethyl acetylenedicarboxylate). Also, stable 5,6,7,8-tetrahydroisoquinolinium dicyanomethylide was isolated and characterized by X-ray diffraction analysis.
    No preview · Article · Oct 2014 · Tetrahedron Letters
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    ABSTRACT: (+)-(2R,3R)-1,1,4,4-Tetraphenylbutane-1,2,3,4-tetraol (TETROL) functions as a highly efficient host for the inclusion of cyclohexanone and 2-, 3- and 4-methylcyclohexanone, all with 1:1 host:guest ratios. Most extraordinarily, the 3- and 4-methyl isomers are uniquely included in their higher energy axial methyl conformations rather than as their more energetically favorable equatorial analogues. In contrast, 2-methylcyclohexanone is included more conventionally in the equatorial methyl conformation. During recrystallization of TETROL from racemic 2- and 3-methylcyclohexanone, some preference is shown by the host for the (R)-enantiomer. In the latter case, this is attributed to a much stronger H-bond between a hydroxyl group of TETROL and the carbonyl group of the (R)-enantiomer (O...O 2.621(2) angstroms) compared with a significantly weaker H-bond to the (S)-enantiomer (3.125(8) angrstroms). In the former instance, hydrogen bond strengths to both enantiomers are similar but the (R)-enantiomer engages in three (guest)CH...pi(host) and three (guest)H...Car(host) contacts while fewer interactions of these types are observed for the (S)-enantiomer. Calculations of geometries of the guest cyclohexanones were determined at the MP2/6-311++G(2df,2p) level and compared with those obtained at the G3(MP2) level. Finally, an interesting correlation between crystal packing indices for the three methylcyclohexanone clathrates and their respective desolvation onset temperatures was identified.
    No preview · Article · Sep 2014 · Chemical Communications
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    ABSTRACT: 7,8,9,10-Tetrahydropyrrolo[2,1-a]isoquinolines were obtained by 1,3-dipolar cycloaddition reactions of their corresponding N-ylides with olefinic (acrylonitrile) and symmetrical or non-symmetrical acetylenic dipolarophiles (methyl/ethyl propiolate, dimethyl acetylenedicarboxylate). Also, stable 5,6,7,8-tetrahydroisoquinolinium dicyanomethylide was isolated and characterized by X-ray diffraction analysis.
    No preview · Article · Sep 2014 · Tetrahedron Letters
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    ABSTRACT: 3-(6-Methoxypyridin-3-yl)-5-(4-methylsulfonyl phenyl)-pyridin-2-amine (MMP) is a member of a novel class of orally active antimalarial drugs. This aminopyridine molecule has shown potent in vitro antiplasmodial activity and in vivo antimalarial activity in Plasmodium berghei-infected mice. The aqueous solubility of this molecule is, however, limited. Thus investigations aimed at improving the physicochemical properties, including solubility, of MMP were accordingly conducted. Five salts of MMP were formed with co-former molecules saccharin, salicylic acid, fumaric acid, oxalic acid and suberic acid, but a cocrystal was obtained when the co-former adipic acid was employed. All these new multicomponent systems have been fully characterised using X-ray diffraction and thermal methods. Semiquantitative, turbidimetric solubility tests in a phosphate-buffered saline solution at a pH of 7.4 were performed on the salts and the cocrystal of MMP. The saccharinate salt, fumarate salt and the cocrystal of MMP proved to have greater solubility than MMP itself. This work illustrates the importance of screening and modifying candidate drug compounds in their preliminary stages of development.
    Preview · Article · Jun 2014 · CrystEngComm
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    ABSTRACT: In this article we present a detailed structural investigation of novel polycyclic pentacyclo[5.4.1.02,6.03,10.05,9]undecane and adamantane propargylamine hybrid molecules. The structural characterization of these compounds was performed using MS, FT-IR and NMR spectroscopy in combination with X-ray diffraction analysis. The single crystal X-ray analyses of four synthons (6, 8–10) are presented; 8-(N)-propargylamino-8,11-oxapentacyclo-[5.4.1.02,6.03,10.05.9]undecane (compound 6 crystallized in the monoclinic system, unit cell parameters: a = 20.737(2) Å; b = 8.127(1) Å; c = 12.606 (1) Å; β = 92.360(2)°; V = 2122.8(3) Å3; Z = 8); 11-hydroxy-(N)-propargyl-8,11-azapentacyclo[5.4.1.02,6.03,10.05.9]undecane (compound 8 crystallized in the monoclinic system, unit cell parameters: a = 7.9624(6) Å; b = 14.9332(6) Å; c = 9.6162(7) Å; β = 109.029(3); V = 1080.9(2) Å3; Z = 4); 1-methyl-11-hydroxy-(N)-propargyl-8,11-azapentacyclo[5.4.1.02,6.03,10.05.9]undecane (compound 9 crystallized in the monoclinic system, unit cell parameters: a = 7.732(1) Å; b = 15.148(2) Å; c = 9.864(1) Å; β = 101.728(3)°; V = 1131.3 (2) Å3; Z = 4); and an adamantane derivative, N,N-dipropargyl-adamantan-1-amine (compound 10 crystallized in the orthorhombic system, unit cell parameters: a = 34.098(4) Å; b = 6.825(1) Å; c = 10.979(1) Å; V = 2555.0(5) Å3; Z = 8). From the X-ray analyses it is clear that the polycyclic structures had different modes of intermolecular interaction and molecular stacking. Compound 9 exhibited a cis configuration between the OH and CH3 moieties as expected in view of potential steric hindrance and the electron density effects of the methyl moiety on the initial amination reaction. These hybrid molecules exhibited significant anti-apoptotic activity and could thus find application as neuroprotective agents. Graphical abstract A series of pentacyclo[5.4.1.02,6.03,10.05,9]undecane- and adamantane-propargylamines were synthesized and characterized by high-resolution MS, FT-IR, 1H-NMR and 13C-NMR spectroscopy and single-crystal X-ray diffraction. These compounds showed promising neuroprotective ability.
    No preview · Article · Apr 2014 · Journal of Chemical Crystallography
  • Susan A. Bourne · Mino R. Caira
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    ABSTRACT: 1.Introduction2.General Classification and Description2.1.Inorganic Hosts and Their Inclusion Compounds2.2.Applications of Inorganic Systems2.3.Organic Hosts and Their Inclusion Compounds2.4.Applications of Organic Systems3.Methods of Characterization
    No preview · Chapter · Mar 2014
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    ABSTRACT: 7,8,9,10-Tetrahydropyrrolo[2,1-a]isoquinolines were obtained by 1,3-dipolar cycloaddition reactions of their corresponding N-ylides with olefinic (acrylonitrile) and symmetrical or non-symmetrical acetylenic dipolarophiles (methyl/ethyl propiolate, dimethyl acetylenedicarboxylate). Also, stable 5,6,7,8-tetrahydroisoquinolinium dicyanomethylide was isolated and characterized by X-ray diffraction analysis.
    No preview · Article · Jan 2014 · Tetrahedron Letters
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    ABSTRACT: The identification and application of (+)-(2R,3R)-1,1,4,4-tetraphenylbutane-1,2,3,4-tetrol (TETROL) as an efficient and selective host compound is described. Computational and single crystal X-ray diffraction analyses revealed that the butane backbone of TETROL adopts a relatively rigid anti-conformation, with the hydroxy groups oriented syn and connected through a cyclic, homodromic arrangement of their O-H bonds. This structure is stabilised through a pair of 1,3-hydrogen bonding interactions. TETROL forms inclusion complexes with pyridine and 3- and 4-methylpyridine, and does so selectively from mixtures of the pyridines. X-ray diffraction (single crystal and powder) and thermal analyses of the inclusion compounds are described.
    No preview · Article · Oct 2013 · Tetrahedron
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    ABSTRACT: Screening for new solid forms of the antihypertensive lisinopril was performed by recrystallization of the commercial form, lisinopril dihydrate, from various solvents and by exposing the product of its dehydration to a series of vapors under controlled conditions. Modifications other than the dihydrate encountered in the study included new anhydrous and amorphous forms, with intrinsic dissolution rates significantly greater than that of the dihydrate. Further physicochemical characterization included constant and programmed temperature powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, and Fourier transform infrared spectroscopy. In the course of this study, the single-crystal X-ray structure of lisinopril dihydrate, [a = 14.550(2), b = 5.8917(8), c = 14.238(2) Å, β = 112.832(3)° at T = 173(2) K, space group P21 , Z = 2], was determined for the first time, revealing its double zwitterionic character in the solid state. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    No preview · Article · Oct 2013 · Journal of Pharmaceutical Sciences
  • Paula M. Uberman · Mino R. Caira · Sandra E. Martin
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    ABSTRACT: The new chiral bis(arsine) ligand N,N'-bis[2'(diphenylarsino)benzoyl]-(1R,2R)-cyclohexanediamine (BiAsBA, 3), based on the backbone of the Trost modular ligand (TML), was synthesized in three steps. A useful approach to introduce the -AsPh2 group on arsine ligands by Pd-catalyzed arsination was used. The molecular structure and configuration of the BiAsBA ligand was determined by single-crystal X-ray crystallography. In the asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate very high to complete conversion and modest enantioselectivity were achieved. Despite the low enantioselectivity obtained, the bis(arsine) ligand BiAsBA showed significant potential, since it provided a higher ee value than the phosphorus-containing homologous "Trost standard ligand" (TSL) with the same substrate.
    No preview · Article · Jun 2013 · Organometallics
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    ABSTRACT: The interaction in the solid state between ciprofloxacin (CIP) and norfloxacin (NOR) was investigated and a new multicomponent molecular complex (COP) was obtained and characterized. It is composed of equimolar quantities of both compounds, according to TLC and 1H NMR data. As single-crystal X-ray analysis showed, COP crystallizes in the triclinic system, space group P(1̅). The asymmetric unit comprises three independent zwitterions (A, B, and C) with contributions of both CIP and NOR, as well as 14.6 water molecules. At the zwitterion A site, the occurrence is about 37% (CIP), 63% (NOR); at the B site, there is predominantly CIP (70%); and at the C site the occurrence is about 43% (CIP) and 57% (NOR), yielding an overall 1:1 CIP-NOR ratio in the crystal. TG data evidenced a one-step loss of solvent (about 18% per COP zwitterion) below 110 °C, confirming the presence of water molecules. The propensity for heteroassociation between CIP and NOR, under the conditions described herein, originated a co-crystal reported for the first time between FQs, and became one of the most interesting aspects of this research.
    Full-text · Article · Mar 2013 · Crystal Growth & Design
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    ABSTRACT: Tizoxanide [2-(hydroxy)-N-(5-nitro-2-thiazolyl)benzamide, TIZ] is a new potent anti-infective agent which may enhance current therapies for leishmaniasis, Chagas disease and viral hepatitis. The aim of this study was to identify the conformational preferences that may be related to the biological activity of TIZ by resolving its crystal structure and characterizing various physicochemical properties, including its experimental vibrational and 13C nuclear magnetic resonance properties, behavior on heating and solubility in several solvents at 25 °C. TIZ crystallizes from dimethylformamide as the carboxamide tautomer in the triclinic system, space group P(−1) (No. 2) with the following unit cell parameters at 173(2) K: a = 5.4110(3) Å, b = 7.3315(6) Å, c = 13.5293(9) Å, α = 97.528(3), β = 95.390(4), γ = 97.316(5), V = 524.41(6) Å3, Z = 2, Dc = 1.680 g/cm3, R1 = 0.0482 and wR2 = 0.0911 for 2374 reflections. This modification of TIZ has a ‘graphitic’ structure and is composed of tightly packed layers of extensively hydrogen-bonded molecules. The various spectroscopic data [Diffuse Fourier transform infrared (DRIFT) and FT-Raman, recorded in the range 3600–500 and 4000–200 cm−1 respectively, and solid-state 13C NMR] were consistent with the structure determined by X-ray crystallography. From DSC, TG and thermomicroscopy, it was concluded that TIZ is thermally stable as a solid and that melting is not an isolated event from the one-step thermal decomposition that it undergoes above 270 °C. This modification of TIZ is practically insoluble in water and slightly soluble in polar aprotic solvents such as dimethylsulfoxide, dimethylformamide and dioxane.
    No preview · Article · Mar 2013 · Journal of Molecular Structure
  • Mino R. Caira
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    ABSTRACT: Polymorphs, solvates, inclusion complexes and co-crystals of active pharmaceutical ingredients (APIs) are four established classes of 'supramolecularly derived' therapeutic agents. Each distinct solid phase in any of these classes contains a given API in an intact molecular form and possesses a unique crystalline structure and hence unique physical properties that warrant careful consideration and monitoring during its isolation, processing, formulation, delivery and storage. Hitherto unknown solid species in these classes are constantly being sought by pharmaceutical scientists because they present new opportunities for drug development. Physicochemical characterization of each new solid form of an API to establish its structure, thermodynamic stability and its relationship to known forms is an essential part of the preformulation phase. Thermal analysis plays a critical role in such characterization, but unequivocal interpretation of the derived experimental data relies on insights afforded by complementary techniques such as spectroscopy (FTIR, Raman, solid-state NMR) and X-ray diffraction. In this review, several recently reported studies highlighting the application of thermal analysis to the four classes of pharmaceutically relevant solids are presented; these studies also reflect the interdependence of characterization methods when applied to 'supramolecularly derived' species.
    No preview · Article · Feb 2013 · ChemInform

Publication Stats

3k Citations
503.72 Total Impact Points

Institutions

  • 1972-2015
    • University of Cape Town
      • Department of Chemistry
      Kaapstad, Western Cape, South Africa
  • 2007-2011
    • Rhodes University
      • Department of Chemistry
      Grahamstad, Eastern Cape, South Africa
  • 2005
    • Port Elizabeth Museum
      Port Elizabeth, Eastern Cape, South Africa
  • 2004
    • Academia Romana
      • Department of Organic Chemistry
      Bucureşti, Hunedoara, Romania