Sreenivasa Reddy Mundla

Sreenivasa Reddy MundlaSreeni Labs Private Limited · Organic Chemistry

· Ph.D
  • About
    Top co-authors
    Followers (5)
    Michael M Lahn
    Narayan Garimella
    Anthony Melvin Crasto
    Avery Sears
    Hong-Yu Li
    Following (13)
    View All
    Lei Yan
    Arindam Chatterjee
    William Seibel
    Michael M Lahn
    Sean R Klopfenstein
    Abraham Thomas
    Robert M Campbell
    Bryan D Anderson
    Charles Heap
    James M Cook
    Research Items (26)
    Visual cycle inhibitors (modulators) have gained significant recognition as potential therapeutics to prevent retinal degeneration. We discovered that all-trans-retinal, a retinoid metabolite naturally produced during visual processing, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, we identified the first-in-class drug candidates that transiently sequester this metabolite. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyl transferase (LRAT) is the enzyme that initially traps vitamin A (retinol) from the circulation and photoreceptor cells to produce the esterified substrate for the second enzyme, retinoid isomerase (RPE65) which converts the all-trans-retinyl ester to an 11-cis-retinol. Thus the pharmacologically active compounds and substrates of LRAT could be selectively delivered to the eye. However, the chemical similarity of LRAT's substrate and RPE65 inhibitors could affect the isomerase and produce delayed dark adaptation, a debilitating visual problem for humans. Here we delineate certain chemical boundaries for LRAT substrate and RPE65 inhibitor specificities together with their protection against retinal degeneration in mice. The American Society for Pharmacology and Experimental Therapeutics.
    [298-12-4] C2H2O3 (MW 74.04) InChI = 1S/C2H2O3/c3-1-2(4)5/h1H,(H,4,5) InChIKey = HHLFWLYXYJOTON-UHFFFAOYSA-N(formaldehyde equivalent in Mannich reaction; reagent and its esters undergo a variety of additions, condensations, and Diels–Alder reactions)Alternate Name: glyoxalic acid; oxoacetic acid.Physical Data: deliquescent prisms; mp 98 °C (anhydrous), 50–52 °C (monohydrate); pKa 2.32.Solubility: sparingly sol ether, alcohol, benzene; v sol water.Form Supplied in: crystalline solid as monohydrate [563-96-2] and in 50% aqueous solution.Preparative Methods: glyoxylic acid is widely available, but the methyl, ethyl, and benzyl esters can be made easily from the ozonolysis of the corresponding maleate and fumarate esters.1Purification: crystallized from water as the monohydrate.Handling, Storage, and Precaution: corrosive and hygroscopic.
    In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.
    A simple and efficient synthesis of dihydropyrrolopyrazole boronic acid intermediate (5) has been developed. Utilization of a three-component Suzuki–Miyaura/etherification with microwave heating led to advanced compound 11 in high yield and with easy purification. Reaction of compound 11 with methanesulfonyl chloride at room temperature furnished the 1,3 O–N rearranged product (12), which is postulated to proceed via an intramolecular mechanism. The outlined synthesis provides a highly efficient and high-yielding route that is amenable to rapid analog synthesis.
    Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.
    A Rh-mediated tandem Pauson–Khand reaction has been developed to provide the desired diastereomer 8a in a 7:1 ratio over the undesired isomer(s), and this has been converted into the [5.8.5] system 11 to provide a potential new route to the ophiobolins.
    [431-03-8] C4H6O2 (MW 86.09) InChI = 1S/C4H6O2/c1-3(5)4(2)6/h1-2H3InChIKey = QSJXEFYPDANLFS-UHFFFAOYSA-N(cyclocondensations; reacts with Wittig reagents; condensations)Alternate Name: biacetyl.Physical Data: mp 2.4 °C; bp 88 °C/760 mmHg; d 0.981 g cm−3; fp <21 °C.Solubility: sol water (25 g/100 mL); miscible with alcohol and ether.Form Supplied in: yellowish green liquid; quinone odor.Purification: dried over anhydrous CaSO4, CaCl2, or MgSO4, then vacuum distilled under nitrogen. The middle fraction is taken and stored at dry ice temperature in the dark (to prevent polymerization).Handling, Storage, and Precautions: highly flammable, moderately toxic.
    [107-22-2] C2H2O2 (MW 58.04) InChI = 1S/C2H2O2/c3-1-2-4/h1-2HInChIKey = LEQAOMBKQFMDFZ-UHFFFAOYSA-N(undergoes condensations and Wittig reactions to form carbo- and heterocycles)Alternate Name: ethanedial.Physical Data: yellow prisms, mp 15 °C; bp 50.4 °C/760 mmHg; d420 1.29 g cm−3.Solubility: sol water, ether, ethanol.Form Supplied in: crystalline trimeric dihydrate (OHCCHO)3·2H2O [4405-13-4], which is nonhygroscopic; also supplied as a 40% aqueous solution which may contain polymerization inhibitors. An addition compound with NaHSO3 serves as a nonaqueous form of glyoxal (monohydrate; [517-21-5]).Purification: for most reactions, can be used without further purification. Anhydrous form should be freshly prepared.1Handling, Storage, and Precautions: should be handled carefully to avoid exposure. Use in a fume hood.
    A new method for the synthesis of 2-halo-6-nitrostyrenes from 2-halo-6-nitrotoluenes is disclosed. Also described is a one-pot process for the synthesis of 2,6-dinitristyrene from 2,6-dinitrotoluene.
    A novel method for the efficient synthesis of 2-arylamino-2-imidazolines is described.
    A novel method for the regioselective synthesis of 4-halo ortho-dinitrobenzene derivatives was developed by reacting various meta-halo nitrobenzenes with urea nitrate in concentrated sulfuric acid.
    A pharmacophore and an alignment rule have previously been reported for BzR agonist ligands. The design and synthesis of 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC, 24, IC50 = 8.1 nM) was based on this pharmacophore. When evaluated in vivo this ligand exhibited anticonvulsant/anxiolytic activity but was devoid of the muscle relaxant/ataxic effects of "classical" 1,4-benzodiazepines (i.e., diazepam). Significantly, 6-PBC 24 also reversed diazepam-induced muscle relaxation in mice. The 3-substituted analogues 40-46 and 48 of 6-PBC 24 and Zk 93423 27(IC50 = 1 nM) were synthesized and evaluated in vitro to determine what affect these modifications would have on the binding affinity at recombinant BzR subtypes. With the exception of the 3-amino ligands 40 and 41, all the beta-carbolines were found to exhibit high binding affinity at BzR sites. The 3-propyl ether derivative 45 was also evaluated in vivo and found to be devoid of any proconvulsant or anticonvulsant activity at doses up to 40 mg/kg. The 6-(1-naphthylmethyloxy) and 6-octyloxy analogues 25, 26, 28, and 29 of 6-PBC 24 were synthesized to further evaluate the proposed alignment of agonists vs inverse agonists in the pharmacophore of the BzR. In addition, ligands 26 and 29 were designed to probe the dimensions of lipophilic pocket L3 at the agonist site. The activity of 29 was evaluated in vivo; however, this analogue elicited no pharmacological effects at doses up to 80 mg/kg. These and other related beta-carbolines were also examined in five recombinant GABAA receptor subtypes. Ligands 52-61 all exhibited moderate to high affinity at GABAA receptors containing alpha1 subunits. These ligands will be useful in further defining the pharmacophore at alpha1 beta3 gamma2 receptors.
    A short, novel, linear triquinane-based strategy, directed towards the synthesis of complex tetracyclic alkaloids of paniculatine and magellanine-type, and culminating in the synthesis of deoxymagellaninone 32 is delineated. The cornerstone of our approach was the utilization of the ‘carbocycle-heterocycle equivalency’ stratagem to generate the N-methylpiperidine ring-D from a cyclopentene precursor, e.g. 35→38. The six-membered ring-A present in the natural products was constructed either through cationic enone-olefin cyclization (25→26) or intramolecular Michael addition (34→35) protocols. Overall, the synthetic effort outlined here is notable for its brevity, conceptual simplicity and desirable levels of regio- and stereoselective control in various steps.
    Little information is available on the actions of β-carboline convulsants on insect GABA receptors or their potential as insecticides. Accordingly, two compounds (3-ethoxy-β-carboline, 3-EBC; dimethoxy-β-carboline-3-methyl ester, DMCM) were studied for their effects on Drosophila melanogaster larval neuron discharge and also in lethality bioassays on adult female D. melanogaster and adult male Blattella germanica. Recordings of nerve spiking in the isolated larval central nervous system showed that 3-EBC and DMCM inhibited nerve discharge, and this inhibitory effect was not additive with that of GABA, confirming that the inhibition was expressed through an action on the GABA receptor. Nerve blockage induced by β-carbolines could not be reversed by picrotoxinin, indicating that there may exist some overlap or negative allosteric coupling between the picrotoxinin and β-carboline binding sites. DMCM and 3-EBC effectively antagonized the effects of exogenously applied GABA in nerve preparations from insecticide-susceptible larvae. In contrast, preparations from the rdl strain of D. melanogaster, which possesses a GABA receptor that is highly resistant to cyclodienes and related convulsants, were less sensitive to the GABA antagonist effect of DMCM. Neither of the β-carbolines produced any appreciable mortality in insects, even when synergized with piperonyl butoxide or S,S,S-tributyl phosphorotrithioate, The toxicity of the β-carbolines is probably limited by their relatively weak effects on the GABA receptor and perhaps also by pharmacokinetic factors. These considerations, coupled with the cross-resistance observed in cyclodiene-resistant insects, suggest that the currently available β-carbolines are not viable as lead compounds for insecticide screening efforts. © 1997 SCI.
    Multidrug resistance (MDR) in neoplastic cells is usually due to decreased cellular retention of drugs such as vincristine or doxorubicin. An ATP-dependent drug efflux pump has been detected in MDR-1-phenotypic cells; inhibition of the MDR pump is probably the primary mechanism for reversal of MDR. Although quinine (SQ1) and quinidine are reversal agents and inhibitors of the MDR pump, the results from in vivo experiments and in vitro experiments with these diastereomers are contradictory. These observations suggest that an oxidized metabolite of SQ1 is a more potent inhibitor of the MDR pump than is the parent compound. The chemical synthesis of the epoxides of SQ1 and quinidine is reported. The epoxy compounds have been tested as inhibitors of the ATP-dependent MDR pump in human CEM/VLB100 cells. The procedure is based on preloading the cells with an inhibitor and a low concentration of a substrate, rhodamine 123 (R123). After several cold rinses, the cell suspension is passed through a filtration-flow apparatus and the R123 in the filtrate (determined by fluorescence measurements) reveals the initial efflux of R123 through the MDR pump. When tested as an inhibitor of the MDR pump, quinine-10,11-epoxide is approximately 8-fold more potent than SQ1.
    The total synthesis of roeharmine 1 as well as an enantiospecific synthesis of (−)-1,2,3,4-tetrahydroroeharmine 2 has been achieved the Pictet-Spengler reaction as a key step. The optical rotation of synthetic (−)-2 was found to be higher than that reported for the natural product. A possible mechanism for the racemization of 2 upon exposure to acid has been proposed and serves as a warning to alkaloid chemists who isolate ring-A alkoxylated indole alkaloids under acidic conditions.
    The concept of carbocycle-heterocycle equivalency has been utilised to assemble the framework of fawcettimine-serratinine group of alkaloids from 1,5-cyclooctadiene through a common tricarbocyclic intermediate 3.
    A synthetic approach towards novel tetraquinane diterpenes of the crinipellin group compounds (4–8) is delineated. The main theme of this approach centres around the use of readily available and adequately functionalised triquinane 10 as the key synthon to which an appropriately substituted five-membered ring can be annulated with concurrent generation of the spiro centre. Consequently, compound 10 was elaborated to the enone 22, which was in turn subjected to cyclopentannulation employing three different intramolecular strategies, viz. photochemical cycloaddition (22→23→24), cationic enone–olefin cyclisation (22→24→27) and radical cyclisation (22→32→27). While five of the six stereogenic centres on the carbocyclic framework of tetraquinane 27 could be correctly set, the C(12)-isopropyl group was epimeric with respect to that in the natural products. Nevertheless, compound 27 was further elaborated to the C20-tetraquinane 40 through chemical modifications in ring D, constituting the first synthesis of the complete skeleton of the criniepellins.
    An approach is outlined for the obtention of the complete tetracyclic skeleton present in the novel lycopodium alkaloids of paniculatine-type.
    Reaction of dichloroketene with 1,5-dimethyl-1,5 COD 6 charters an eventful course to furnish novel tricyclic ketone 10, through the intermediacy of tricyclic hydroxy olefin 9, in which the two carbon atoms of dichloroketene form a bridge across the eight mem-bered ring.
    Top co-authors