Conformation-activity correlations for chemotactic tripeptide analogs incorporating dialkyl residues with linear and cyclic alkyl sidechains at position 2

Five stereochemically constrained analogs of the chemotactic tripeptide incorporating 1-aminocycloalkane-1-carboxylic acid (Ac(n)c) and alpha,alpha-dialkylglycines (Deg, diethylglycine; Dpg, n,n-dipropylglycine and Dbg, n,n-dibutylglycine) at position 2 have been synthesized. NMR studies of peptides For-Met-Xxx-Phe-OMe (Xxx = Ac(7)c, I; Ac(8)c, II; Deg, III; Dpg, IV and Dbg, V; For, formyl) establish that peptides with cycloalkyl residues, I and II, adopt folded beta-turn conformations in CDCl3 and (CD3)(2)SO. In contrast, analogs with linear alkyl sidechains, III-V, favour fully extended (C-5) conformations in solution. Peptides I-V exhibit high activity in inducing beta-glucosaminidase release from rabbit neutrophils, with ED(50) values ranging from 1.4-8.0 x 10(-11)M. In human neutrophils the Dxg peptides III-V have ED(50) values ranging from 2.3 x 10(-8) to 5.9 x 10(-10) M, with the activity order being V > IV > III. While peptides I-IV are less active than the parent. For-Met-Leu-Phe-OH, in stimulating histamine release from human basophils, the Dbg peptide V is appreciably more potent, suggesting its potential utility as a probe for formyl peptide receptors.

Hantzsch 1,4-dihydropyridine esters and analogs: candidates for generating reproducible one-dimensional packing motifs

Examination of the symmetric Hantzsch 1,4-dihydropyridine ester derivatives of the prototypical nifedipine molecule indicates the tendency of this class of molecule to form a common packing motif. Crystal structure analysis of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic diesters and analogs reveals that they form extended chains, characterized as the C(6) packing motif, via intermolecular (amine) N-H...O=C (C3,C5 carbonyl) hydrogen bonds. In addition, all the prepared derivatives also satisfy the basic structural requirements for their high binding efficiency to the receptor. The reproducible C(6) packing motif observed among these compounds has a use in the design of solid-state materials.

Aspects of tautomerism. 13. Alkaline hydrolysis of .gamma.-, .delta.-, and .epsilon.-keto esters and their desoxy analogs. Geometrical constraints on keto participation

The rates of alkaline hydrolysis of methyl &benzoylpropionate (I), methyl y-benzoylbutyrate (11) and methyll6-benzoylvalerate (In) decrease in the order I > I1 > III. Keto participation is the predominant pathway in the case of y-keto esters. Evidence has also been obtained for keto participation in the case of 6-keto esters, whereas no such evidence is available in the case of r-keto esters studied.

Synthesis of new 4-isopropylthiazole hydrazide analogs and some derived clubbed triazole, oxadiazole ring systems - A novel class of potential antibacterial, antifungal and antitubercular agents

In the present study a series of 4-isopropylthiazole-2-carbohydrazide analogs, derived clubbed oxadiazole-thiazole and triazole-thiazole derivatives have been synthesized and characterized by IR, H-1 NMR, C-13 NMR, elemental and mass spectral analyses. The synthesized compounds were evaluated for their preliminary in vitro antibacterial, antifungal and antitubercular activity against Mycobacterium tuberculosis H(37)Rv strain by broth dilution assay method. The synthesized compounds 7a, 7b, 7d and 4 showed an antitubercular efficacy considerably greater than that of the parent 4-isopropyl-1,3-thiazole-2-carbohydrazide 1, suggesting that the substituted 4-isopropylthiazole-2-carbohydrazide moiety plays an important role in enhancing the antitubercular properties of this class of compounds. Compounds 2c, 3, 4, 6d, 7a and 7b exhibited good or moderate antibacterial and antifungal activity. Compounds 4 and 7b showed appreciable cytotoxicity at a concentration of 250 mu M.

Design, Development, Synthesis, and Docking Analysis of 2-substituted Triclosan Analogs as Inhibitors for Plasmodium falciparum Enoyl-ACP Reductase

A structure-based approach has been adopted to develop 2'substituted analogs of triclosan. The Cl at position 2' in ring B of triclosan was chemically substituted with other functional groups like NH2, NO2 and their inhibitory potencies against PfENR were determined. The binding energies of the 2' substituted analogs of triclosan for enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum were determined using Autodock. Based on the autodock results, we synthesized the potential compounds. The IC50 and inhibition constant (K-i) of 2' substituted analogs of triclosan were determined against purified PfENR. Among them, two compounds,2-(2'-Amino-4'-chloro-phenoxy)-5-chloro-phenol (compound 4) and 5-chloro-2-(4'-chloro-2'-nitro-phenoxy)-phenol) (compound 5) exhibited good potencies. Compound 4 followed uncompetitive inhibition kinetics with crotonoyl CoA and competitive with NADH. It was shown to have an IC50 of 110 nM; inhibition constant was 104 nM with the substrate and 61 nM with the cofactor. IC50 Of compound 5 was determined to be 229 nM. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture. (C) 2009 IUBMB IUBMB Life, 61(11):1083-1091, 2009.

Conformationally restricted formyl methionyl tripeptide chemoattractants: a three-dimensional structure-activity study of analogs incorporating a C alpha,alpha-dialkylated glycine at position 2

The conformationally restricted CHO-L-Met-Xxx-L-Phe-OY (where Xxx = Aib, Ac3c, Ac5c, Ac6c, and Ac7c; Y = H, Me) tripeptides, analogs of the chemoattractant CHO-L-Met-L-Leu-L-Phe-OH, have been synthesized in solution by classical methods and fully characterized. Compounds were compared to determine the combined effect of backbone conformational preferences and side-chain bulkiness on the relation of three-dimensional structure to biological activity. Each peptide was tested for its ability to induce granule enzyme secretion from rabbit peritoneal polymorphonuclear leukocytes. In parallel, a conformational analysis on the CHO-blocked peptide and their tertbutyloxycarbonylated synthetic precursors was performed in the crystal state and in solution using X-ray diffraction, infrared absorption, and 1H nuclear magnetic resonance. The biological and conformational data are discussed in relation to the proposed model of the chemotactic peptide receptor of rabbit neutrophils.

Interaction of synthetic analogs of distamycin and netropsin with nucleic acids. Does curvature of ligand play a role in distamycin-DNA interactions?

Distamycin and netropsin, a class of minor groove binding nonintercalating agents, are characterized by their B-DNA and A-T basespecific interactions. To understand the CQI I ~OIT~ ~ I ~ ~aOnMd ~c hemical basis of the above specificities, the DNA-binding characteristics of a novel synthetic analogue of distamycin have been studied. The analogue, mPD derivative, has the requisite charged end groups and a number of potential hydrogen-bonding loci equal to those of distamycin. The difference in the backbone curvatures of the ligands, distamycin, the mPD derivative, and NSC 101327 (another structurally analogous compound),is a major difference between these ligands. UV and CD spectrosoopic studies reported here show the following salient features: The mPD derivative recognizes only B-DNA, to which it binds via the minor groove. On the other hand, unlike distamycin, it binds with comparable affinities to A-T and G-C base pairs in a natural DNA. These DNA-binding properties are compared with those reported earlier for distamycin and NSC 101327 [Zimmer, Ch., & Wahnert, U. (1986) Prog. Biophys. Mol. Biol. 47, 31-1121. The backbone structures of these three ligands were compared to show the progressive decrease in curvatures in the order distamycin, mPD derivative, and NSC 101327. The plausible significance of the backbone curvature vis-&vis the characteristic B-DNA and AT-specific binding of distamycin is discussed. To our knowledge, this is the first attempt (with a model synthetic analogue) to probe the possible influence of backbone curvature upon the specificity of interactions of the distamycin class of groove-binding ligands with DNA.

Alkaloid synthesis: stereoselective approach towards fawcettimine-serratinine group of lycopodium alkaloids

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.

Synthesis of DEF ring skeleton of naulafine alkaloid

6, 8-Dichloro-4, 5-dihydro-2-methyl-[2, 7]acenaphthyridin-1-one (5), obtained from the. reaction of 5-cyano-2, 6-dihydroxy-3, 4-cyclopentenopyridine with Vilsmeier reagent, has been transformed to the key synthon 4a in two steps.

A novel structural derivative of natural alkaloid ellipticine, MDPSQ, induces necrosis in leukemic cells

DNA intercalating molecules are promising chemotherapeutic agents. In the present study, a novel DNA intercalating compound of pyrimido4',5':4,5]selenolo(2,3-b)quinoline series having 8-methyl-4-(3 diethylaminopropylamino) side chain is studied for its chemotherapeutic properties. Our results showed that 8-methyl-4-(3 diethylaminopropylamino) pyrimido 4',5':4,5] selenolo(2,3-b)quinoline (MDPSQ) induces cytotoxicity in a time- and concentration-dependent manner on leukemic cell lines. Both cell cycle analysis and tritiated thymidine assays revealed that MDPSQ affects DNA replication. Treatment with MDPSQ resulted in both elevated levels of DNA strand breaks and repair proteins, further indicating its cytotoxic effects. Besides, Annexin V/PI staining revealed that MDPSQ induces cell death by triggering necrosis rather than apoptosis.