| Part I. In order to search for a more selective antitumor agent, more than 30 different tryprostatin A analogs have been synthesized and evaluated on tsFT210 cells. The modification of areas (A), (B), (C), and (D) has been realized. In order to study mechanism of action, the irreversible inhibitors 6-azidotryprostatin B 170 and 6-isothiocyanate analog 169 were prepared. According to analysis of the SAR, the 6-methoxy group must be maintained or at least a substituent kept at this position of the indole ring A. Modification of the Na-function on the indole nucleus to furnish Na-phenyl-tryprostatin A 130 and Na-allyl-tryprostatin A 131 inhibited cell cycle progression of tsFT210 cells in the G1 or G2/M phase. Replacement of the 2-isoprenyl group with other lipophilic substituents at position-2 of 1 provided active analogs. Of course, different amino acids could be incorporated into the proline portion of the dipeptide unit to provide active analogs, although all the new analogs are less potent that tryprostatin A 1.;Recent work with Joel Turner indicated tryprostatin A 1 was a specific inhibitor of breast cancer resistance protein (BCRP). Studies indicated tryprostatin A 1 was able to reverse topotecan efflux and demonstrated that topotecan efflux was caused by BCRP. Therefore, tryprostatin A 1 may play a very important role in the study of multiple drug resistance in human patients. Therefore, tryprostatin A 1 may play a very important role in the study of multiple drug resistance in human patients. Important work continues in this area.;Part II. Pharmacophore/receptor models for 6 recombinant GABAA/BzR sub-types (alphaxbeta3gamma2, x = 1--6) have been established via an SAR ligand mapping approach. This study was based on the affinities of more than 400 BzR ligands at 6 distinct (alpha1--6beta3gamma2) recombinant GABAA/BzR receptor subtypes from at least fourteen different structural families. Examination of the included volumes indicated the shapes of binding pockets for alpha1, alpha2 and alpha3 subtypes were very similar to each other. Region L2 for the alpha5 containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region LDi , in contrast, appeared to be larger in the alpha1 subtype than in the other subtypes. Moreover, region L3 in the alpha6 subtype was either very small or nonexistent in this diazepam insensitive "DI" subtype as compared to the other subtypes. (Abstract shortened by UMI.). |
