I. Structure-based molecular modeling and synthesis of indole derivatives as non-phenolic analogues of mycophenolic acid. II. 3D-QSAR studies using CoMFA on homotropane and tropane derivatives as dopamine transporter and serotonin transporter ligands.

摘要

I. Mycophenolic Acid (MPA) is a known potent inhibitor for inosine 5′-monophosphate dehydrogenase (IMPDH). Although MPA exhibited antineoplastic action on cell lines, the rapid metabolic conversion of its phenolic hydroxyl into inactive glucuronide prohibited any in vivo anticancer effect. Any replacement of such phenol with bioisoteric group resulted in loss of potency.; The presented work involves the structure-based molecular modeling and synthesis of two indole 3-carboxamide derivatives as non-phenolic indole analogues of mycophenolic acid.; The computer modeling using the SYBYL software examined binding opportunities of the indole derivatives with the crystal structure of the Chinese hamster and the Human type-II IMDHs. The synthesis of the title ( E)-6-(3-carboxamoyl-6-methoxy-5-methylindole-7-yl)-4-methyl-4-hexenoic acid was accomplished using two synthetic approaches: (a) preparing indole 3-nitrile key intermediate via enamination then Heck palladium coupling but the two key reaction were low yielding; (b) the same key indole intermediate was synthesized in a more convergent approach depending on 1,3-sigmatropic rearrangement as a key reaction. Using the later strategy, the synthesis of title compound was accomplished in 20 steps (0.17% overall yield).; II. A series of 3-aryl-2-propionylazabicyclo[3.2.2]-nonane derivatives were synthesized using the Davies' strategy for building the tropane nucleus. The compounds were tested against both dopamine transporter protein (DAT) and serotonin transporter protein (SERT). This 3.2.2 system would serve the understanding of the binding mode of cocaine analogues via the dislocation of the tropane's nitrogen as well as groups at C2 and C3.; This project involved the use of CoMFA to explore the 3D-QSAR of mixed data set of 17 homotropane and 9 tropane derivatives. The database construction involved conformational search techniques to optimize the structures. Database alignment was based on the rigid cycloheptane portion of the nuclei. The PLS analyses using leave one out method showed high predictive ability of the model (Q2 = 0.869 for DAT and 0.895 for SERT).; The CoMFA contour maps confirmed that the C3 aryl group is the most contributing part of the molecule to the binding potency and the selectivity. The C2 substituents may have very minor interactions with the receptor site and it mostly affects the activity indirectly via controlling the conformation of the C3 aromatic ring. CoMFA did not correlate the change in binding properties between tropane and homotropane to change in the nitrogen location.