Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2020-10-26 , DOI: 10.1016/j.bmc.2020.115816 Liezel A Lumangtad 1 , Elisa Claeys 2 , Sunil Hamal 1 , Amarawan Intasiri 3 , Courtney Basrai 1 , Expedite Yen-Pon 1 , Davison Beenfeldt 1 , Kurt Vermeire 2 , Thomas W Bell 1
CADA compounds selectively down-modulate human cell-surface CD4 protein and are of interest as HIV entry inhibitors and as drugs for asthma, rheumatoid arthritis, diabetes and some cancers. Postulating that fusing a pyridine ring bearing hydrophobic substituents into the macrocyclic scaffold of CADA compounds may lead to potent compounds with improved properties, 17 macrocycles were synthesized, 14 with 12-membered rings having an isobutylene head group, two arenesulfonyl side arms, and fused pyridine rings bearing a para substituent. The analogs display a wide range of CD4 down-modulating and anti-HIV potencies, including some with greater potency than CADA, proving that a highly basic nitrogen atom in the 12-membered ring is not required for potency and that hydrophobic substituents enhance potency of pyridine-fused CADA compounds. Cytotoxicities of the new compounds compared favorably with those of CADA, showing that incorporation of a pyridine ring into the macrocyclic scaffold can produce selective compounds for potently down-modulating proteins of medicinal interest.
中文翻译:
吡啶融合的环三氮杂二磺酰胺 (CADA) 化合物的合成和抗 HIV 和人类分化簇 4 (CD4) 下调效力
CADA 化合物选择性地下调人类细胞表面 CD4 蛋白,并作为 HIV 进入抑制剂和哮喘、类风湿性关节炎、糖尿病和某些癌症的药物受到关注。假设将带有疏水性取代基的吡啶环融合到 CADA 化合物的大环支架中可能会产生具有改进性能的有效化合物,合成了 17 个大环,14 个具有具有异丁烯头基团、两个芳烃磺酰基侧臂和稠合吡啶的 12 元环带有对位取代基的环。这些类似物显示出广泛的 CD4 下调和抗 HIV 效力,其中一些效力高于 CADA,证明效力不需要 12 元环中的强碱性氮原子,并且疏水取代基增强了抗 HIV 的效力吡啶稠合的 CADA 化合物。