Akimova Akimova, Rychkov G N, Grin M A, Filippova N A, Golovina G V, Durandin N A, Vinogradov A M, Kokrashvili T A, Mironov A F, Shtil A A, Kuzmin V A
N.M. Emanuel Institute of Biochemical Physics, Kosygina Str., 4, Moscow, 119334, Russia.
Petersburg Nuclear Physics Institute, Orlova Roscha, Gatchina, Leningrad district, 188300, Russia ; St.Petersburg State Polytechnical University, Politekhnicheskaya Str., 29, St. Petersburg, 195251, Russia.
Acta Naturae. 2015 Jan-Mar;7(1):109-16.
Optimization of the chemical structure of antitumor photosensitizers (PSs) is aimed at increasing their affinity to a transport protein, albumin and irreversible light-induced tumor cell damage. Bacteriopurpurinimide derivatives are promising PSs thanks to their ability to absorb light in the near infrared spectral region. Using spectrophotometry, we show that two new bacteriopurpurinimide derivatives with different substituents at the N atoms of the imide exocycle and the pyrrole ring A are capable of forming non-covalent complexes with human serum albumin (HSA). The association constant (calculated with the Benesi-Hildebrand equation) for N-ethoxybacteriopurpurinimide ethyloxime (compound 1) is higher than that for the methyl ether of methoxybacteriopurpurinimide (compound 2) (1.18×10(5) M-1 vs. 1.26×10(4) M(-1), respectively). Molecular modeling provides details of the atomic interactions between 1 and 2 and amino acid residues in the FA1 binding site of HSA. The ethoxy group stabilizes the position of 1 within this site due to hydrophobic interaction with the protein. The higher affinity of 1 for HSA makes this compound more potent than 2 in photodynamic therapy for cultured human colon carcinoma cells. Photoactivation of 1 and 2 in cells induces rapid (within a few minutes of irradiation) necrosis. This mechanism of cell death may be efficient for eliminating tumors resistant to other therapies.
优化抗肿瘤光敏剂（PSs）的化学结构旨在提高其与转运蛋白白蛋白的亲和力以及光诱导的肿瘤细胞不可逆损伤。细菌紫质酰亚胺衍生物因其能够在近红外光谱区域吸收光而成为有前景的PSs。通过分光光度法，我们发现两种在酰亚胺外环和吡咯环A的氮原子上具有不同取代基的新型细菌紫质酰亚胺衍生物能够与人血清白蛋白（HSA）形成非共价复合物。N - 乙氧基细菌紫质酰亚胺乙肟（化合物1）的缔合常数（用贝内西 - 希尔德布兰德方程计算）高于甲氧基细菌紫质酰亚胺甲醚（化合物2）（分别为1.18×10⁵ M⁻¹和1.26×10⁴ M⁻¹）。分子模拟提供了化合物1和2与HSA的FA1结合位点中的氨基酸残基之间原子相互作用的细节。由于与蛋白质的疏水相互作用，乙氧基稳定了化合物1在该位点内的位置。化合物1对HSA的更高亲和力使其在培养的人结肠癌细胞的光动力治疗中比化合物2更有效。化合物1和2在细胞中的光激活诱导快速（照射后几分钟内）坏死。这种细胞死亡机制可能对消除对其他疗法耐药的肿瘤有效。
