Anderson W K, Kasliwal R, Houston D M, Wang Y S, Narayanan V L, Haugwitz R D, Plowman J
Department of Medicinal Chemistry, School of Pharmacy, State University of New York at Buffalo 14260, USA.
J Med Chem. 1995 Sep 15;38(19):3789-97. doi: 10.1021/jm00019a008.
Platinum (II) and platinum (IV) coordination complexes derived from beta-silyl-substituted amines were prepared. The solubility of selected complexes in water and physiological saline was measured, and the effect of the beta-silicon on the reactivity of the complex in aqueous solution was determined by HPLC. The stabilities of selected silyl complexes were compared to the carbon analogues. The cyclic complexes 2a ("silaplatin") and its Pt(IV) analogue, 2b, were very active against L1210 leukemia in vivo. Both the platinum (II) complex 2a and the platinum (IV) complex 2b produced a significant number of cures over the dose range 10-40 mg/kg. The platinum (II) complex 2a, silaplatin, was very active in vivo against an L1210 leukemia subline that was resistant to cisplatin; 2a was also active, when given ip, against ic implanted L1210. The cyclobutanedicarboxylic acid complex 3c was synthesized; this complex was active against both cisplatin sensitive and resistant L1210 leukemia but was less potent than the analogous dichloro compound 2a. The acyclic platinum (II) and platinum (IV) complexes 1a,b were synthesized and unexpectedly found to be inactive in vivo against L1210 leukemia. More lipophilic silaplatin analogues were prepared--Pt(II) complex 2c and Pt(IV) complex 2d have one additional methylene carbon compared to 2a,b, whereas Pt(II) complex 2e and Pt(IV) complex 2f have two additional methylene carbons. Cyclization of the alkyl groups attached to the silicon gave the spiro bicyclic Pt(II) complexes 10a and 11a and the Pt(IV) complexes 10b and 11b.
制备了源自β-硅基取代胺的铂（II）和铂（IV）配位络合物。测量了所选络合物在水和生理盐水中的溶解度，并通过高效液相色谱法确定了β-硅对络合物在水溶液中反应活性的影响。将所选硅基络合物的稳定性与碳类似物进行了比较。环状络合物2a（“硅铂”）及其铂（IV）类似物2b在体内对L1210白血病具有很高的活性。铂（II）络合物2a和铂（IV）络合物2b在10-40mg/kg的剂量范围内都产生了大量的治愈病例。铂（II）络合物2a，硅铂，在体内对顺铂耐药的L1210白血病亚系具有很高的活性；当腹腔注射时，2a对皮下植入的L1210也有活性。合成了环丁烷二羧酸络合物3c；该络合物对顺铂敏感和耐药的L1210白血病均有活性，但效力低于类似的二氯化合物2a。合成了无环铂（II）和铂（IV）络合物1a，b，意外地发现它们在体内对L1210白血病无活性。制备了更多亲脂性的硅铂类似物——与2a，b相比，铂（II）络合物2c和铂（IV）络合物2d多一个亚甲基碳，而铂（II）络合物2e和铂（IV）络合物2f多两个亚甲基碳。连接到硅上的烷基环化得到了螺双环铂（II）络合物10a和11a以及铂（IV）络合物10b和11b。
