Deciphering the origins of molecular toxicity of combretastatin A4 and its glycoconjugates: interactions with major drug transporters and their safety profiles in vitro and in vivo

Abstract

Cellular uptake and transport mechanisms directly correlate with the drug-like profiles of lead compounds. To decipher the molecular origin of the toxicity of combretastatin A4 (CA4), an important microtubule targeting agent, we investigated the interactions between CA4 and six key drug transporters, namely hOAT1, hOAT3, hOCT1, hOCT2, hOATP1B3, and hOATP2B1. Three combretastatin-based glycoconjugates, namely ,, and with glucose, mannose, and galactose respectively, were synthesized and their and biological characteristics were evaluated. CA4 exhibited significant inhibition against hOAT3 and hOATP2B1, moderate inhibition of hOAT1 and hOCT2, and weak inhibitory effects on hOCT1 and hOATP1B3. Compared to CA4, the inhibitory activities of on the six transporters were minimal. The glycoconjugates were found to have a superior safety profile with their maximum tolerated dose (MTD) values exhibiting a 16-34-fold increase compared to CA4. Given the drawbacks of CA4, the enhanced solubility and safety profiles of CA4 glycoconjugates augur well for further investigation into these intriguing candidates' efficacy.

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“…That gives opportunities in the design of platforms that deliver drug molecules to cancer cells [120]. Huang et al also used the idea of using gluco-conjugates to improve the effectiveness of the drug [133]. The authors proved that conjugates of CA-4 with glucose, mannose, and galactose have improved water solubility and a better safety profile with the 16-34-fold increased maximum tolerated dose values compared to CA-4 [133].…”