Novel Hybrids of 3-Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents with Collateral Sensitivity against MCF-7/ADR

  • J Med Chem. 2022 Jul 14;65(13):9328-9349. doi: 10.1021/acs.jmedchem.2c00608.
Zhihui Yu  1 ,  Mengru Li  2 ,  Ke Wang  1  3 ,  Yuting Gu  2 ,  Shiqi Guo  1 ,  Weijie Wang  1 ,  Yulei Ma  2 ,  Hongrui Liu  2 ,  Ying Chen  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 3. Pharmaceutical Sciences Division, School of Pharmacy,, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin 53705-2222, United States.
PMID: 35737669 DOI: 10.1021/acs.jmedchem.2c00608
Abstract

Twenty-three new coumarin-furoxan hybrids were synthesized, which exhibited nanomole antiproliferation activities in A2780, A2780/CDDP, MCF-7/ADR, and MDA-MB-231. Among them, compound 9 showed the strongest collateral sensitivity to MCF-7/ADR with 499-fold potency compared with MCF-7. Notably, the solubility of compound 9 increased 70-fold compared with the lead 2. And preliminary pharmacological studies displayed that compound 9 obviously increased Rh123 accumulation in MCF-7/ADR and released NO to produce ROS in lysosomes, which were able to damage lysosomal membrane and induce Apoptosis. These results reasonably explained that the collateral sensitivity of compound 9 to MCF-7/ADR was closely related to P-gp-mediated lysosome damage and Apoptosis. Additionally, compound 9 showed a very weak cytotoxicity both in MCF-10A and hERG potassium channels and had a desirable safety in ion cyclotron resonance (ICR) mice. Hence, compound 9 was merited to further study for developing a desirable candidate against MDR MCF-7/ADR via a potential mechanism of collateral sensitivity in MDR Cancer cell lines.