Discovery of 4-Aryl-4H-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-Based High Throughput Screening Assay. 4. Structure–Activity Relationships of N-Alkyl Substituted Pyrrole Fused at the 7,8-Positions

Abstract

In our continuing effort to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the structure-activity relationship (SAR) of alkyl substituted pyrrole fused at the 7,8-positions. A methyl group substituted at the nitrogen in the 7-position of the pyrrole ring led to a series of potent apoptosis inducers with potency in the low nanomolar range. These compounds were also found to be low nanomolar or subnanomolar inhibitors of cell growth, and they inhibited tubulin polymerization, indicating that methylation of the 7-position nitrogen does not change the mechanism of action of these chromenes. Compound 2d was identified as a highly potent apoptosis inducer with an EC50 value of 2 nM and a highly potent inhibitor of cell growth with a GI50 value of 0.3 nM in T47D cells.

Synthesis, antitumor screening and cell cycle analysis of novel benzothieno[3,2-b]pyran derivatives

“…Searching the literature revealed the outstanding activity of 4-aryl-4H-chromenes as apoptotic inducers and cytotoxic agents. Thus, 4-aryl-4H-chromenes (like compounds IV and V) were reported as potent apoptosis inducer in human breast cancer cells T47D [18][19][20] . Their SAR study indicated that both the 2-amino and the 3-cyano groups were essential for the antitumor activity.…”

“…Their SAR study indicated that both the 2-amino and the 3-cyano groups were essential for the antitumor activity. Replacement of the cyano with ester group or replacement of the amino with amide or urea groups decreased the antitumor activity 19,20 .…”

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

“…Recently, two major classes of small molecular compounds inducing apoptosis have been developed as potential anticancer agents, including the caspase-inhibiting isatin derivatives [113][114][115] and the apoptosis-inducing 4-aryl-4H-chromens, which inhibit tubulin polymerization and bind at the colchicine binding site [115][116][117]. Several articles have reported the synthesis and biological evaluation of radiolabeled isatin derivatives for imaging of apoptosis using PET [114,[118][119][120][121][122][123].…”

An efficient synthesis of hemiaminal of indoles by using tetrabutylammonium fluoride (TBAF) in water as a reusable reaction media

“…Some hemiaminals of indole and related N-heterocycles possess anti-tumor activity (2,3). Additionally, these compounds have been utilized as labile precursor for in-situ generation of formaldehyde (4Á6) and a selfcleavable linker for drug molecules to improve their bioavailability (7,8).…”