Leftheris K, Kline T, Vite G D, Cho Y H, Bhide R S, Patel D V, Patel M M, Schmidt R J, Weller H N, Andahazy M L, Carboni J M, Gullo-Brown J L, Lee F Y, Ricca C, Rose W C, Yan N, Barbacid M, Hunt J T, Meyers C A, Seizinger B R, Zahler R, Manne V
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
J Med Chem. 1996 Jan 5;39(1):224-36. doi: 10.1021/jm950642a.
Analogs of CVFM (a known nonsubstrate farnesyltransferase (FT) inhibitor derived from a CA1A2X sequence where C is cysteine, A is an aliphatic residue, and X is any residue) were prepared where phenylalanine was replaced by (Z)-dehydrophenylalanine, 2-aminoindan-2-carboxylate, 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Tic), and indoline-2-carboxylate. The greatest improvement in FT inhibitory potency was observed for the Tic derivative (IC50 = 1 nM); however, this compound was ineffective in blocking oncogenic Ras-induced transformation of NIH-3T3 fibroblast cells. A compound was prepared in which both the Cys-Val methyleneamine isostere and the Tic replacement were incorporated. This derivative inhibited FT with an IC50 of 0.6 nM and inhibited anchorage-independent growth of stably transformed NIH-3T3 fibroblast cells by 50% at 5 microM. Replacing the A1 side chain of this derivative with a tert-butyl group and replacing the X position with glutamine led to a derivative with an IC50 of 2.8 nM and an EC50 of 0.19 microM, a 26-fold improvement over (S*,R*)-N-[[2-[N-(2-amino-3-mercaptopropyl)-L-valyl]-1,2,3,4- tetrahydro-3-isoquinolinyl]carbonyl]-L-methionine. This derivative, (S*,R*)-N-[[2-[N-(2-amino-3-mercaptopropyl)-L-tert-leucyl]-1,2,3,4 - tetrahydro-3-isoquinolinyl]-carbonyl]-L-glutamine, was evaluated in vivo along with (S*,R*)-N-[[2-[N-(2-amino-3- mercaptopropyl)-L-tert-leucyl]-1,2,3,4-tetrahydro-3- isoquinolinyl]carbonyl]-L-methionine methyl ester for antitumor activity in an athymic mouse model implanted ip with H-ras-transformed rat-1 tumor cells. When administered by injection twice a day at 45 mg/kg for 11 consecutive days, both compounds showed prolonged survival time (T/C = 142-145%), thus demonstrating efficacy against ras oncogene-containing tumors in vivo.
制备了CVFM（一种已知的非底物法尼基转移酶（FT）抑制剂，源自CA1A2X序列，其中C为半胱氨酸，A为脂肪族残基，X为任意残基）的类似物，其中苯丙氨酸被（Z）-脱氢苯丙氨酸、2-氨基茚-2-羧酸、1,2,3,4-四氢异喹啉-3-羧酸（Tic）和吲哚啉-2-羧酸取代。观察到Tic衍生物的FT抑制效力有最大程度的提高（IC50 = 1 nM）；然而，该化合物在阻断致癌性Ras诱导的NIH-3T3成纤维细胞转化方面无效。制备了一种同时引入了半胱氨酸-缬氨酸甲亚胺类似物和Tic取代基的化合物。该衍生物抑制FT的IC50为0.6 nM，在5 microM时可抑制稳定转化的NIH-3T3成纤维细胞的非锚定依赖性生长达50%。将该衍生物的A1侧链替换为叔丁基并将X位替换为谷氨酰胺，得到一种IC50为2.8 nM、EC50为0.19 microM的衍生物，比（S*,R*）-N-[[2-[N-(2-氨基-3-巯基丙基)-L-缬氨酰基]-1,2,3,4-四氢-3-异喹啉基]羰基]-L-甲硫氨酸提高了26倍。该衍生物（S*,R*）-N-[[2-[N-(2-氨基-3-巯基丙基)-L-叔亮氨酰基]-1,2,3,4-四氢-3-异喹啉基]羰基]-L-谷氨酰胺与（S*,R*）-N-[[2-[N-(2-氨基-3-巯基丙基)-L-叔亮氨酰基]-1,2,3,4-四氢-3-异喹啉基]羰基]-L-甲硫氨酸甲酯一起在植入H-ras转化的大鼠-1肿瘤细胞的无胸腺小鼠模型中评估抗肿瘤活性。当以45 mg/kg的剂量每天注射两次，连续注射11天时，两种化合物均显示出生存时间延长（T/C = 142 - 145%），从而证明了其在体内对含ras癌基因肿瘤的疗效。
