Springer C J, Dowell R, Burke P J, Hadley E, Davis D H, Blakey D C, Melton R G, Niculescu-Duvaz I
Cancer Research Campaign Centre for Cancer Therapeutic, Institute of Cancer Research, Sutton, Surrey, U.K.
J Med Chem. 1995 Dec 22;38(26):5051-65. doi: 10.1021/jm00026a013.
Sixteen novel potential prodrugs derived from phenol or aniline mustards and their 16 corresponding drugs with ring substitution and/or different alkylating functionalities were designed. The [[[4-]bis(2-bromoethyl)-(1a), [[[4-[bis(2-iodoethyl)-(1b), and [[[4-[(2-chloroethyl)-[2-(mesyloxy)ethyl]amino]phenyl]oxy] carbonyl]-L-glutamic acids (1c), their [[[2- and 3-substituted-4-[bis(2-chloroethyl)amino]phenyl]oxy]carbonyl]-L- glutamic acids (1e-1), and the [[3-substituted-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl]-L- glutamic acids (1o-r) were synthesized. They are bifunctional alkylating agents in which the activating effect of the phenolic hydroxyl or amino function is masked through an oxycarbonyl or a carbamoyl bond to a glutamic acid. These prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in antibody-directed enzyme prodrug therapy (ADEPT). The synthesis of the analogous novel parent drugs (2a-r) is also described. The viability of a colorectal cell line (LoVo) was monitored with the potential prodrugs and the parent drugs. The differential in the cytotoxicity between the potential prodrugs and their corresponding active drugs ranged between 12 and > 195 fold. Compounds 1b-d,f,o exhibited substantial prodrug activity, since a cytotoxicity differential of > 100 was achieved compared to 2b-d,f,o respectively. The ability of the potential prodrugs to act as substrates for CPG2 was determined (kinetic parameters KM and kcat), and the chemical stability was measured for all the compounds. The unsubstituted phenols with different alkylating functionalities (1a-c) proved to have the highest ratio of the substrates kcat:KM. From these studies [[[4-[bis(2-iodoethyl)amino]phenyl]oxy]carbonyl]-L-glutamic acid (1b) emerges as a new ADEPT clinical trial candidate due to its physicochemical and biological characteristics.
设计了16种源自苯酚或苯胺氮芥的新型潜在前药及其16种具有环取代和/或不同烷基化功能的相应药物。合成了[[[4-]双(2-溴乙基)-(1a)、[[[4-[双(2-碘乙基)-(1b)和[[[4-[(2-氯乙基)-[2-(甲磺酰氧基)乙基]氨基]苯基]氧基]羰基]-L-谷氨酸(1c)、它们的[[[2-和3-取代-4-[双(2-氯乙基)氨基]苯基]氧基]羰基]-L-谷氨酸(1e-1)以及[[3-取代-4-[双(2-氯乙基)氨基]苯基]氨基甲酰基]-L-谷氨酸(1o-r)。它们是双功能烷基化剂，其中酚羟基或氨基功能的活化作用通过与谷氨酸的氧羰基或氨基甲酰基键被掩盖。这些前药设计为在抗体导向酶前药疗法(ADEPT)中，通过预先给予与细菌酶羧肽酶G2(CPG2)偶联的单克隆抗体，在肿瘤部位被激活为其相应的苯酚和苯胺氮芥药物。还描述了类似新型母体药物(2a-r)的合成。用潜在前药和母体药物监测结肠直肠癌细胞系(LoVo)的活力。潜在前药与其相应活性药物之间的细胞毒性差异在12至>195倍之间。化合物1b-d、f、o表现出显著的前药活性，因为与2b-d、f、o相比，细胞毒性差异分别达到>100。测定了潜在前药作为CPG2底物的能力(动力学参数KM和kcat)，并测量了所有化合物的化学稳定性。具有不同烷基化功能的未取代酚(1a-c)被证明具有最高的底物kcat:KM比值。从这些研究中，[[[4-[双(2-碘乙基)氨基]苯基]氧基]羰基]-L-谷氨酸(1b)因其理化和生物学特性而成为一种新的ADEPT临床试验候选药物。
