Comparative molecular field analysis as a tool to evaluate mode of action of chemical hybridization agents.

The 3D-QSAR method of comparative molecular field analysis (CoMFA) was applied to three patent families of chemical hybridization agents (CHAs) in the MON21200 class of chemistry. The models for each CHA family gave good correlations between the variations in log percent male sterility and in the steric-electrostatic properties of the patent set. For all CHA families, observed sterility rates are generally higher for the sodium salts than for the corresponding esters. This is consistent with our CoMFA models which show that negative charge is favored in the region of the carboxylate group. The CoMFA models also indicated that for the MON21200 family increased steric bulk at the 4-position on the phenyl ring is associated with enhanced activity. However, for the RH0007 and the HYBRID families, male sterility is generally enhanced with increased steric bulk at the 2- or 3-position on the phenyl ring. Although the models cannot provide unambiguous conclusions about a common mode of action, similarities in the CoMFA contour maps provided some clues for a common agrophore for these three CHA families.

Molecular mechanics studies on dipeptide models of diphenylalanine and its derivatives.

As a part of our studies on the structure and conformations of peptidomimetics, we present conformational energy calculations on model peptides with (a) diphenyl alanine and its tricyclic derivatives and (b) triphenyl alanine residues using molecular mechanics and conformational analysis methods. The energies are calculated as a function of the backbone torsions (phi and psi), and the results are presented in terms of isoenergy contours in the phi-psi space. The low-energy models adopt conformations characteristic of a variety of regular structures such as the alpha-helix, gamma-turn and polyproline-II-type three- and four-fold helices. The conformational preferences in the model peptides with diphenyl alanine and its tricyclic derivatives are sensitive to the side-chain torsion, with some similarities to the corresponding preferences of L-Ala dipeptide. The energy profile of the model peptide with triphenyl alanine is similar to that of the model peptide with Tle (tert-leucine) residue. The results of our studies have implications in the design of conformationally constrained peptidomimetics with structures in the beta- and alpha-helical regions.

Conformational studies on model dipeptides of Gly, L-Ala and their C alpha-substituted analogs.

As a part of the development of conformational guidelines for the design of metabolically altered peptidomimetics, we present conformational energy calculations on model dipeptide compounds with glycine (Gly), L-alanine (Ala), alpha-aminoisobutyric acid (Aib), L-tert-butylglycine (Tle), L-phenylglycine (Phg), (alpha, alpha)-diphenylglycine (D phi g), L-2-aminobutyric acid (Abu), 2-amino-2-ethylbutyric acid (Deg), L-2-amino-2-vinylacetic acid (Ava) and (alpha, alpha)-divinylglycine (Dvg). The energy calculations have been made using molecular mechanics methods with a force field derived from MM2. The salient features are expressed in terms of conformational energy plots, drawn as a function of the backbone torsion angles phi(Ci'-1-Ni-Ci alpha i-Ci') and psi(Ni-Ci alpha -C'-N(i+1)). The low-energy structures of these compounds are qualitatively consistent with the X-ray crystal structure analyses of peptides and peptidomimetics. They are also in agreement with the results of the solution-phase studies carried out by NMR and IR techniques. The results obtained have important implications in the design of conformationally restricted peptidomimetics.

Synthesis, topoisomerase I inhibitory activity, and in vivo evaluation of 11-azacamptothecin analogs.

A series of analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay. The parent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedlander condensation between the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidine and optically active tricyclic ketone 7. Compound 8 had activity approximately twice that of (20S)-camptothecin in the calf thymus topoisomerase I cleavable complex assay. Compounds were prepared wherein the 11-aza nitrogen atom was quaternized as either the corresponding N-oxide or methyl iodide. Compounds with quaternized N-11 showed improved water solubility and were equipotent to the clinically investigated camptothecin analog topotecan in the cleavable complex assay. These compounds were evaluated in vivo in nude mice bearing HT-29 human colon carcinoma xenografts. The analog 11-aza-(20S)-camptothecin 11-N-oxide was found to significantly retard tumor growth when compared to untreated controls. Finally, 7,10-disubstituted 11-azacamptothecin analogs were synthesized using Pd(0) coupling reactions of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in turn were available from a Friedlander condensation of the novel bromopyridine derivatives 17a and 17b with 7. Among the 10-substituted series, a number of analogs displayed extremely high in vitro potency against topoisomerase I and improved aqueous solubility. A significant number of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumor xenografts. The most effective of these proved to be (S)-11-aza-7-ethyl-10-(aminohydroximinomethyl)camptothecin trifluoracetic acid salt (27), a potent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays. A comparison between in vitro enzyme data and in vivo data from nude mouse studies in other compounds in this series revealed a poor overall correlation between topoisomerase inhibition in vitro and antitumor efficacy in vivo.

Mean geometry of the thiopeptide unit and conformational features of dithiopeptides and polythiopeptides.

The mean geometry of the thiopeptide [Ca-N-C(=S)-Ca] unit has been derived from an analysis of X-ray crystal structure data, as well as MM2 and Gaussian 80/82 calculations. The conformational flexibilities of dithiopeptides with glycl- and alanyl-side chains have been investigated by molecular mechanics. Minimum energy conformations were examined using interactive computer graphics molecular modeling techniques. Alanyl-dithiopeptide substitution within an oligopeptide results in considerable restriction of conformational freedom whereas the effect is minimal for glycyl-dithiopeptide substitution. Polyglycyl-thiopeptide adopts a left-handed three or fourfold or right-handed threefold helical structure with favorable interchain C = S...H-N hydrogen bond interactions. A poly-L-alanyl-thiopeptide prefers a left-handed threefold poly-L-proline-like helical structure.

Salmonella infections in patients with acquired immunodeficiency syndrome.

Salmonella infections occurred in six patients with acquired immunodeficiency syndrome (AIDS) and one patient with probable AIDS. The immune system defects increase the susceptibility of patients with AIDS to salmonella infections. Recognition of salmonellosis in patients with AIDS is important because of a high propensity of this organism to invade the bloodstreams of these patients, and because, unlike other infections in patients with AIDS, this infection can be easily treated.