Integrated Drug Discovery, Isotope Chemistry, Sanofi R&D, 13 Quai Jules Guesde, 94403, Vitry sur Seine, France.
Chembiochem. 2021 Jul 15;22(14):2424-2429. doi: 10.1002/cbic.202100080. Epub 2021 Jun 1.
Antibody drug conjugates (ADCs) are one of the most promising technologies to treat cancer as they combine the specificity of an antibody with the high potency of a cytotoxic molecule such as tomaymycin derivatives, which are DNA-interactive antitumor antibiotics previously isolated from bacterial broth. The multistep chemical synthesis of some tomaymycin derivatives is complicated because their structures contain a reactive imine bond. Therefore, we turned to biosynthesis to obtain C radiolabelled tomaymycin derivative to support ADME studies. Following Hurley's work (J. Antibiotics 1977, 30, 349-370; Antimicrob. Agents Chemother. 1979, 15, 42-45; Acc. Chem. Res. 1980, 13, 263-269), the C radiolabel was incorporated efficiently in one step from radiolabelled tyrosine using the strain Streptomyces sp. FH6421. This process has been further optimized by using anthranilic acid as radiolabelled precursor, leading to one of the highest incorporation levels of radiochemical precursors published to date. This biosynthetic strategy is the fastest way to access such radiolabelled precursors.
抗体药物偶联物 (ADC) 是治疗癌症最有前途的技术之一，因为它们将抗体的特异性与细胞毒性分子的高效性结合在一起，例如托马霉素衍生物，它是以前从细菌培养液中分离出来的具有 DNA 相互作用的抗肿瘤抗生素。由于其结构中含有反应性亚胺键，因此一些托马霉素衍生物的多步化学合成较为复杂。因此，我们转向生物合成来获得 C 放射性标记的托马霉素衍生物，以支持 ADME 研究。在 Hurley 的工作之后（J. Antibiotics 1977, 30, 349-370; Antimicrob. Agents Chemother. 1979, 15, 42-45; Acc. Chem. Res. 1980, 13, 263-269），使用链霉菌 sp. FH6421 从放射性标记的酪氨酸一步高效地掺入了 C 放射性标记物。通过使用邻氨基苯甲酸作为放射性标记前体，进一步优化了该过程，从而得到了迄今为止报道的放射性化学前体掺入水平最高的方法之一。这种生物合成策略是获得此类放射性标记前体的最快方法。
