Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug CHNQD-01255 with Potent Anti-Hepatocellular Carcinoma Efficacy In Vivo

Abstract

Brefeldin A (BFA), a well-known natural Arf-GEFs inhibitor, is effective against hepatocellular carcinoma (HCC), while the poor solubility, serious toxicity, and short half-life limit its potential. Herein, distinct corresponding prodrugs of BFA, including esters 1–15, carbonates 16–24 and 30–32, and carbamates 25–29, were synthesized and evaluated. CHNQD-01255 (16) with improved aqueous solubility (15–20 mg/mL) demonstrated favorable pharmacokinetic profiles. It behaved as expected by undergoing rapid conversion to BFA in vivo, and achieved sufficient high plasma exposure, prolonged half-life, as well as the improved bioavailability of BFA (F = 18.96%). Meanwhile, CHNQD-01255 significantly suppressed tumor growth (TGI = 61.0%) at a dose of 45 mg/kg (p.o.) in the xenograft model. Notably, the improved safety profile of CHNQD-01255 (MTD > 750 mg/kg, p.o.) was confirmed to be superior to that of BFA (MTD < 506 mg/kg). Overall, CHNQD-01255 may serve as a safe and effective new anti-HCC prodrug.

Exploring Retrograde Trafficking: Mechanisms and Consequences in Cancer and Disease

“…The well-established RT inhibitor, BFA, is known to have poor bioavailability in vivo, which has hindered its clinical use [187]. However, derivatives of BFA have shown anti-cancer activity against a plethora of cancer types, with most recent work targeting cervical, breast and hepatocellular cancers, with improved bioavailability [188][189][190][191][192]. Other methods to circumvent this issue are centred on improvement to drug delivery, such as that by Zhang et al who are using nanomicelles to improve the delivery of BFA [193][194][195][196].…”

Design and Synthesis of Brefeldin A-Isothiocyanate Derivatives with Selectivity and Their Potential for Cervical Cancer Therapy

“…However, its poor pharmacokinetic properties and remarkable toxicity seriously hindered its clinical application [19][20][21][22]. Hence, BFA is a promising lead compound to be modified and BFA derivatives were designed and synthesized to overcome its defects [23][24][25][26]. Isothiocyanates (ITCs) are produced by enzymatic hydrolysis of glucosinolates, important secondary metabolites in Brassicaceae [27,28].…”

A Terphenyllin Derivative CHNQD-00824 from the Marine Compound Library Induced DNA Damage as a Potential Anticancer Agent

“…Therefore, marine natural products have consistently proved to be valuable resources for developing anticancer leads. Investigating new bioactive natural products and their derivatives from marine fungi is a significant and ongoing research focus in our laboratory [19][20][21][22][23]. As part of our continuous efforts to search for biologically active secondary metabolites from marine-derived fungi, terphenyllin was obtained from Aspergillus sp.…”

“…Among them, two compounds-Terphenyllin and 3′-(isopentyloxy)-2′,5′-dimethoxy-[1′,1′:4′,1′-terphenyl]-4,4"-diol-not only showed strong α-glucosidase inhibitory activity, but also had relatively higher therapeutic indices, with the potential to be promising leads [24]. Additionally, eight compounds were also found to have cytotoxic Investigating new bioactive natural products and their derivatives from marine fungi is a significant and ongoing research focus in our laboratory [19][20][21][22][23]. As part of our continuous efforts to search for biologically active secondary metabolites from marinederived fungi, terphenyllin was obtained from Aspergillus sp.…”