Synthetic approaches towards novel isoform selective pi3k inhibitors and their biological activities against prostate cancer cells, 2018
Wazeerud-Din, Idris
2010-2019
The development of novel imidazopyridines, which includes both tetrahydroimidazo[1,5-a]pyridine (rIMP) and imidazo[1,5-a]pyridine (IMP) was investigated using conventional and microwave induced procedures that afforded compounds at high yield of 88-96%. rIMP was synthesized using a two-step procedure that involved the microwave synthesis of IMP, then the reduction of the pyridine moiety of the fused imidazopyridine rings using 10% Pd/C and hydrazine monohydrate. The microwave synthesis of imidazopyridines involved the one pot reaction of 2-benzoylpyridine, substituted benzaldehyde and ammonium formate in acetic acid under open vessel microwave conditions, which resulted in products within 40 minutes. Novel PEG-IMP development, involved the synthesis of ethylene glycol tethered benzaldehydes and IMPs using traditional Williamson etherification synthesis, which afforded products at a high yield of 92-95%. We have then shown IMP and rIMP roles in its antiproliferative property towards PCa cells, specificity in inhibiting PI3K isoforms, and structural motifs interaction with different residues in the kinase binding domain of the class I PI3K isoforms. The antiproliferative property towards PC3 cells shows increased activity with compounds containing pyridyl group on carbon 3 of the imidazo[1,5-a]pyridine parent moiety with signs of toxicity to PC3 within 24 hours of incubation and at 1 ?M of the parent compound. Furthermore, the IMPs were tested against five prostate cellular lines: PC3, RWPE1, D145, LNCaP and LNCaP C81. IMPs showed little activity towards RWPE1 and increased activity towards PC3 cells. We determined that functionalizing the phenyl group at position 1 increased the efficacy of rIMP compared to the IMP. After showing increased toxicity to PC3 cells, it was important to investigate the mechanism in which IMP pose toxicity towards PC3 cells. The biochemical assay showed that rIMP was more effective in inhibiting PI3K? isoform compared to both pan inhibitor wortmannin and IMP. Both IMP and rIMP inhibited more than 60% of PI3K? isoform activity at nanomolar concentrations. After showing IMPs affinity to PI3K isoforms, we investigated the binding interactions rIMP and IMP towards the PI3K isoforms using MOE molecular modeling software. KEY TERMS: BioOrganic Chemistry, Prostate Cancer, Imidazopyridine, Molecular Docking, Phosphatidylinositol-(4, 5)-bisphosphate 3-kinase, Biochemistry, Cancer Biology, Heterocyclic Compounds, Medicinal-Pharmaceutical Chemistry
text
application/pdf
2018-08-08
dissertation
Doctor of Philosophy (PhD)
Clark Atlanta University
Chemistry
Bu, Xiu-Ren Khan, Shafiq Williams, Myron
Georgia--Atlanta
http://hdl.handle.net/20.500.12322/cau.td:2018_wazeerud_din_idris_j
