Vinblastine 20′ Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance,Journal of Medicinal Chemistry

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Vinblastine 20′ Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-31 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00958
John C. Lukesh ₁ , Daniel W. Carney ₁ , Huijun Dong ₁ , R. Matthew Cross ₁ , Vyom Shukla ₁ , Katharine K. Duncan ₁ , Shouliang Yang ₁ , Daniel M. Brody ₁ , Manuela M. Brütsch ₁ , Aleksandar Radakovic ₁ , Dale L. Boger ₁

Affiliation

A series of 180 vinblastine 20′ amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure–activity relationships and a structural model were developed in the studies which provided many such 20′ amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.

中文翻译：

长春碱20'酰胺：合成类似物，可维持或提高效价并同时克服Pgp衍生的外流和抵抗力

从市售原料中分三步制备了一系列180种长春碱20'酰胺，系统地探索了分子中通常无法接近的位点，从而获得了强大的功能化策略。在研究中开发了明确的结构-活性关系和结构模型，提供了许多这样的20'酰胺，这些酰胺表现出显着的甚至某些显着的效力增强，许多表现出了针对过表达Pgp的抗性癌细胞系的活性进一步改善，以及长春碱类似物的重要子集，针对配对的一对长春碱敏感和耐药（Pgp过表达）细胞系，其活性几乎没有差异。效能的提高与目标微管蛋白的结合亲和力直接相关，

更新日期：2017-08-31

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