Köhler Sebastian C, Vahdati Sahel, Scholz Matthias S, Wiese Michael
Pharmazeutisches Institut, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Pharmazeutisches Institut, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Eur J Med Chem. 2018 Feb 25;146:483-500. doi: 10.1016/j.ejmech.2018.01.012. Epub 2018 Jan 11.
An overexpression of the transmembrane ATP-binding cassette transporter G2 (ABCG2, BCRP) in cancer tissues is supposed to play a role in the multidrug resistance (MDR) of tumors resulting in an inefficient chemotherapy. Therefore, co-administration of selective and non-toxic ABCG2 inhibitors is a promising strategy for improving the efficacy of chemotherapy by blocking ABCG2-mediated export of the cytostatic drugs. In the present study, we designed a small library of 38 novel compounds containing a heteroaryl-phenyl scaffold possessing several (bioisosteric) moieties, and twelve new precursors. We investigated the library for ABCG2 inhibition, for the selectivity against MDR-involved efflux pump ABCB1 (P-gp) and for toxicity. Structure activity relationship (SAR) studies revealed that, at least a phenylheteroaryl-phenylamide scaffold is necessary for observing an ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a high potency (IC = 61 nM)), selectivity, low intrinsic toxicity and reversed the ABCG2-mediated drug resistance in presence of only 0.1 μM.
跨膜ATP结合盒转运体G2（ABCG2，BCRP）在癌组织中的过表达被认为在肿瘤的多药耐药（MDR）中起作用，导致化疗效果不佳。因此，联合使用选择性且无毒的ABCG2抑制剂是一种有前景的策略，可通过阻断ABCG2介导的细胞毒性药物外排来提高化疗疗效。在本研究中，我们设计了一个包含38种新型化合物的小型文库，这些化合物含有具有多个（生物电子等排体）部分的杂芳基-苯基支架，以及12种新的前体。我们研究了该文库对ABCG2的抑制作用、对涉及MDR的外排泵ABCB1（P-糖蛋白）的选择性以及毒性。构效关系（SAR）研究表明，至少一个苯基杂芳基-苯基酰胺支架对于观察到ABCG2抑制是必要的。4-甲氧基-N-（2-（2-（6-甲氧基吡啶-3-基）-2H-四唑-5-基）苯基）苯甲酰胺（43）表现出高效力（IC = 61 nM）、选择性、低内在毒性，并且在仅存在0.1 μM时就能逆转ABCG2介导的耐药性。
