Human estrogen receptor α antagonists, part 2: Synthesis driven by rational design, in vitro antiproliferative, and in vivo anticancer evaluation of innovative coumarin-related antiestrogens as breast cancer suppressants

Human Estrogen Receptor α Antagonists. Part 1: 3-D QSAR-Driven Rational Design of Innovative Coumarin-Related Antiestrogens as Breast Cancer Suppressants through Structure-Based and Ligand-Based Studies

“… a The designed compounds SB predicted activities against ERα by the N probe 3-D QSAR model. b The designed compounds LB predicted activities against ERα by the N probe 3-D QSAR model. c The designed compounds experimentally predicted activities against ERα …”

“…Furthermore, the assessment of effective SB and ligand-based (LB) alignment rules was shown to be useful tools to dissect the chemical determinants for the potential ERα-based anticancer activity as well as to predict the potency of untested ligands. The 3-D QSAR models and the alignment rules were externally assessed by means of newly designed coumarin-based compounds as ERα antagonists that were promptly synthesized and confirmed as SERMs . Other coumarins, like 3-phenyl-7-hydroxybenzopyranones ( i.e ., 7-hydroxy-2 H -chromen-2-ones) SP500263 , , BL-16d , and BL-18d (Figure ), as well as 3-aryl-4-aryloxy-2 H -chromen-2-ones, behaved as SERMs, while oxyphenylpropenoic acid derivatives 5AK2 (PDB entry ID) and SS5020 (Figure ) were SERDs. − …”

“…To the best of the authors’ knowledge, this is the first report describing ligand/receptor recognition patterns of ERα antagonists by means of maximal use of structural information gathered from unrelated compounds all cocrystallized with either WT or MUT ERα receptors. The developed 3-D QSAR models coupled with consensus SB/LB alignment assessments (AA) led to the design of new coumarin-based potential ERα antagonists ( 3DQ-1a to 3DQ-1e ), that were promptly synthesized, and the in vitro and in vivo testing confirmed the as potent ERα antagonists endowed with anticancer activity . Notably, from biological data, derivatives 3DQ-4a , 3DQ-2a , 3DQ-1a , 3DQ-1b , 3DQ-2b , and 3DQ-3b represent potential new lead candidates for BC clinical trials …”

“…The developed 3-D QSAR models coupled with consensus SB/LB alignment assessments (AA) led to the design of new coumarin-based potential ERα antagonists ( 3DQ-1a to 3DQ-1e ), that were promptly synthesized, and the in vitro and in vivo testing confirmed the as potent ERα antagonists endowed with anticancer activity . Notably, from biological data, derivatives 3DQ-4a , 3DQ-2a , 3DQ-1a , 3DQ-1b , 3DQ-2b , and 3DQ-3b represent potential new lead candidates for BC clinical trials …”

Antitumor and multikinase inhibition activities of some synthesized coumarin and benzofuran derivatives

“…[32][33][34] It was solely reported that the coumarin-like derivatives administration blocked MCF-7 cells in the irreversible (senescent and differentiated) G0 state of cell cycle arrest. [35] S C H E M E 2 Synthesis of the target benzofuran derivatives (15)(16)(17)(18)(19). Reagents and reaction conditions: In addition, we will screen our interesting compounds for potential off-target toxicity and/or strong covalent binding to the target protein kinases in a future advanced investigation.…”