Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety

Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.

Synthesis and cytotoxic activity evaluation of 8-substituted quercetin derivatives / 国际药学研究杂志

Objective: To synthesize 8-substituted quercetin derivatives and test their cytotoxicity on human cancer cell lines, so as to find out hit or lead compounds via structure activity relationship(SAR)analysis. Methods: Using rutin as the raw material, quercetin was obtained by the acid hydrolysis of rutin, and the 8-substituted quercetin derivatives, 3a-3h, were synthesized via the whole hydroxyl protection of quercetin and then halogenation, followed by the Suzuki coupling or heck coupling reaction. The in vitro inhibitory activity of these derivatives was assayed by the MTT method using human cancer HepG2, HT-29 and K562 cell lines. Results and Conclusion: Eight new target compounds, 3a-3h, were synthesized, and their structures were confirmed by the 1H NMR, 13C NMR and MS data. The inhibitory effect of 3b-3h on HepG2 cell line, 3b and 3d on HT-29 cell line, and 3b-3d and 3f-3h on K562 cell line has remarkably and significantly enhanced than that of quercetin, and the present research results provide a suggestive preliminary SAR.

Pharmacokinetic evaluation, molecular docking and in vitro biological evaluation of 1, 3, 4-oxadiazole derivatives as potent antioxidants and STAT3 inhibitors / 药物分析学报

1, 3, 4-Oxadiazole derivatives (4a–5f) were previously synthesized to investigate their anticancer properties. However, studies relating to their antioxidant potential and signal transducer and activator of transcription (STAT) inhibition have not been performed. We investigated previously synthesized 1, 3, 4-oxadiazole de-rivatives (4a–5f) for various radical scavenging properties using several in vitro antioxidant assays and also for direct inhibition of STAT3 through molecular docking. The data obtained from various antioxidant assays such as 2, 2,-diphenyl-1-picrylhydrazyl radical (DPPH), nitric oxide, hydrogen peroxide, and superoxide anion radical revealed that among al the derivatives, compound 5e displayed high antioxidant activities than the standard antioxidant L-ascorbic acid. Additionally, the total reduction assay and antioxidant capacity assay further confirmed the antioxidant potential of compound 5e. Furthermore, the molecular docking studies performed for all derivatives along with the standard inhibitor STX-0119 showed that binding energy re-leased in direct binding with the SH2 domain of STAT3 was the highest for compound 5e (-9.91kcal/mol). Through virtual screening, compound 5e was found to exhibit optimum competency in inhibiting STAT3 activity. Compound 5e decreased the activation of STAT3 as observed with Western blot. In brief, compound 5e was identified as a potent antioxidant agent and STAT3 inhibitor and effective agent for cancer treatment.