Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany.
Technische Universität Dresden, School of Science, Faculty of Chemistry and Food Chemistry, Mommsenstraße 4, 01069 Dresden, Germany.
J Med Chem. 2023 Mar 23;66(6):3818-3851. doi: 10.1021/acs.jmedchem.2c01360. Epub 2023 Mar 3.
The potential of designing irreversible alkyne-based inhibitors of cysteine cathepsins by isoelectronic replacement in reversibly acting potent peptide nitriles was explored. The synthesis of the dipeptide alkynes was developed with special emphasis on stereochemically homogeneous products obtained in the Gilbert-Seyferth homologation for C≡C bond formation. Twenty-three dipeptide alkynes and 12 analogous nitriles were synthesized and investigated for their inhibition of cathepsins B, L, S, and K. Numerous combinations of residues at positions P1 and P2 as well as terminal acyl groups allowed for the derivation of extensive structure-activity relationships, which were rationalized by computational covalent docking for selected examples. The determined inactivation constants of the alkynes at the target enzymes span a range of >3 orders of magnitude (3-10 133 M s). Notably, the selectivity profiles of alkynes do not necessarily reflect those of the nitriles. Inhibitory activity at the cellular level was demonstrated for selected compounds.
研究了通过在可逆作用的强肽腈中进行等电子取代来设计半胱氨酸组织蛋白酶不可逆炔抑制剂的潜力。特别强调了立体化学均匀产物的二肽炔的合成，这些产物是通过 Gilbert-Seyferth 同系化反应获得的，用于 C≡C 键形成。合成了 23 种二肽炔和 12 种类似的腈，并研究了它们对组织蛋白酶 B、L、S 和 K 的抑制作用。在位置 P1 和 P2 以及末端酰基上的许多残基组合允许得出广泛的构效关系，通过对选定实例的计算共价对接对其进行了合理化。在靶酶中，炔的失活常数的范围跨越了 3 个数量级以上（3-10133 M s）。值得注意的是，炔的选择性谱不一定反映出腈的选择性谱。已证明选定化合物在细胞水平上具有抑制活性。
