N-Heterocycle based Degraders (PROTACs) Manifesting Anticancer Efficacy: Recent Advances.

Proteolysis Targeting Chimeras (PROTACs) technology has emerged as a promising strategy for the treatment of undruggable therapeutic targets. Researchers have invested a great effort in developing druggable PROTACs; however, the problems associated with PROTACs, including poor solubility, metabolic stability, cell permeability, and pharmacokinetic profile, restrict their clinical utility. Thus, there is a pressing need to expand the size of the armory of PROTACs which will escalate the chances of pinpointing new PROTACs with optimum pharmacokinetic and pharmacodynamics properties. N- heterocycle is a class of organic frameworks that have been widely explored to construct new and novel PROTACs. This review provides an overview of recent efforts of medicinal chemists to develop N-heterocycle-based PROTACs as effective cancer therapeutics. Specifically, the recent endeavors centred on the discovery of PROTACs have been delved into various classes based on the E3 ligase they target (MDM2, IAP, CRBN, and other E3 ligases). Mechanistic insights revealed during the biological assessment of recently furnished Nheterocyclic- based PROTACs constructed via the utilization of ligands for various E3 ligases have been discussed.

Design, synthesis, and biological activity of dual monoamine oxidase A and heat shock protein 90 inhibitors, N-Methylpropargylamine-conjugated 4-isopropylresorcinol for glioblastoma.

Monoamine oxidase A (MAO A) and heat shock protein 90 (HSP90) inhibitors have been shown to decrease the progression of glioblastoma (GBM) and other cancers. In this study, a series of MAO A/HSP90 dual inhibitors were designed and synthesized in the hope to develop more effective treatment of GBM. Compounds 4-b and 4-c are conjugates of isopropylresorcinol (pharmacophore of HSP90 inhibitor) with the phenyl group of clorgyline (MAO A inhibitor) by a tertiary amide bond substituted with methyl (4-b) or ethyl (4-c) group, respectively. They inhibited MAO A activity, HSP90 binding, and the growth of both TMZ-sensitive and -resistant GBM cells. Western blots showed that they increased HSP70 expression indicating reduced function of HSP90, reduced HER2 and phospho-Akt expression similar to MAO A or HSP90 inhibitor itself. Both compounds decreased IFN-γ induced PD-L1 expression in GL26 cells, suggesting they can act as immune checkpoint inhibitor. Further, they reduced tumor growth in GL26 mouse model. NCI-60 analysis showed they also inhibited the growth of colon cancer, leukemia, non-small cell lung and other cancers. Taken together, this study demonstrates MAO A/HSP90 dual inhibitors 4-b and 4-c reduced the growth of GBM and other cancers, and they have potential to inhibit tumor immune escape.

Protective effects of 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates on vascular cognitive impairment.

A series of 10,11-dihydro-5H-dibenzo [b,f]azepine hydroxamates (4-15) were synthesized, behaving as histone deacetylase inhibitors, and examined for their influence on vascular cognitive impairment (VCI), which correlated with dementia. The results revealed that (E)-3-(4-(((3-(3-chloro-10,11-dihydro-5H-dibenzo [b,f]azepin-5-yl)propyl)amino)methyl)phenyl)-N-hydroxy-acrylamide (13) increases cerebral blood flow (CBF), attenuates cognitive impairment, and improves hippocampal atrophy in in vivo study. It is also able to increase the level of histone acetylation (H3K14 or H4K5) in the cortex and hippocampus of chronic cerebral hypoperfusion (CCH) mice; as a result, it could be a potential HDAC inhibitor for the treatment of vascular cognitive impairment.