A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

Abstract

(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.

Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases

“… [ 487 ] [ 377 ] [ 488 ] TrxR TrxR-interfering drug delivery system (based on RGD-PEG-PUSeSe-PEG-RGD self-assembling micelles)→TrxR→Cancer Se-methylselenocysteine (SMC)→TrxR→AD (NCT01497431, etc.) Butaselen (BS)→TrxR1→Hepatocellular carcinoma BBSKE (Ethaselen)→TrxR1→Cancer ACZ2→TrxR1→Gastric cancer Ethaselen→TrxR1→Lung cancer [ 360 ] [ 489 ] [ 490 ] [ 491 ] [ 492 ] [ 493 ] Michael receptor TrxR [ 6 ]-dehydroshogaol→TrxR→Cancer DVD-445 and its extended analogues→TrxR→Cancer [ 494 ] [ 495 ] Quinazoline derivatives TXNIP Quinazoline derivatives (D-2 & C-1)→TXNIP→Diabetes [ 496 ] Imidazole derivatives Trx1 PX-12 (1-methylpropyl 2-imidazolyl disulfide)→Trx1→Cancer [ 497 ] Benzopyrane derivatives Trx & TrxR SIMR1281→Trx & TrxR→Cancer [ 498 ] Other compounds and therapeutic methods Trx Ac-Cys-Pro-Cys-amide (thioredoxin-mimetic peptide)→Atherosclerosis Ascorbate & menadione→Trx→Cancer HSA-Trx→Trx→ND, PD, Cardiomyopathy PPa@GA/DSPE-PEG2K NPs→Trx→Cancer Au nanoclusters→...…”