Kizu R, Nakanishi T, Miyazaki M, Tashiro T, Noji M, Matsuzawa A, Eriguchi M, Takeda Y, Akiyama N, Kidani Y
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Anticancer Drugs. 1996 May;7(3):248-56. doi: 10.1097/00001813-199605000-00003.
In order to develop orally active antitumor platinum complexes, several cyclohexanediamine-Pt(IV) complexes of a general formula trans,cis,cis-[Pt(IV) (OCOCnHn+1)2 (oxalato)(1R,2R-cyclohexanediamine)] were synthesized by derivatizing oxaliplatin [Pt(II)(oxalato)(1R,2R-cyclohexanediamine), I-OHP], which is a potent antitumor cyclohexanediamine-Pt(II) complex we have prepared and now undergoing clinical trials. The I-OHP derivatives were found to be stable, lipophilic and reduced to yield I-OHP, an active species, quantitatively by ascorbate in vitro. All the derivatives were antitumor active against mouse lymphocytic leukemia L1210 when given i.p. In particular, trans-bis-valerato-oxalato-1R,2R-dach-Pt(IV), C5-OHP, showed markedly high activity. C5-OHP also exhibited significant antitumor activity against L1210 when orally administered. C5-OHP was considered to be a suitable candidate for the oral cancer chemotherapy agent to be developed.
为了开发口服活性抗肿瘤铂配合物，通过对奥沙利铂[Pt(II)(草酸根)(1R,2R-环己二胺)，I-OHP]进行衍生化，合成了几种通式为反式,顺式,顺式-[Pt(IV)(OCOCnHn+1)2(草酸根)(1R,2R-环己二胺)]的环己二胺-Pt(IV)配合物，奥沙利铂是我们制备的一种有效的抗肿瘤环己二胺-Pt(II)配合物，目前正在进行临床试验。发现I-OHP衍生物稳定、亲脂，在体外可被抗坏血酸定量还原生成活性物质I-OHP。所有衍生物经腹腔注射给药时，对小鼠淋巴细胞白血病L1210均具有抗肿瘤活性。特别是反式-双戊酸根-草酸根-1R,2R-二氨基环己烷-Pt(IV)，C5-OHP，显示出显著的高活性。C5-OHP经口服给药时，对L1210也表现出显著的抗肿瘤活性。C5-OHP被认为是一种适合开发的口服癌症化疗药物候选物。
