K-102

Previously, we have reported that the newly synthesized octahedral Pt(IV) compound, trans,cis-Pt(acetato)(2)Cl(2)(1,4-butanediamine), K101 and trans,cis-Pt(trifluoroacetato)(2)Cl(2)(1,4-butanediamine), K102 showed potent antitumor activities in vitro and in vivo. In order to compare the nephrotoxicity of the newly synthesized Pt(IV) complexes, K102 and K102 with cisplatin, we performed various tests.

We performed a single dose acute toxicity test for LD(50) values determination, biochemical assays in blood serum, acid phosphatase enzyme histochemistry and transmission electron microscopic studies in renal proximal tubular cells in mice in vivo. The route of drugs administration is intraperitoneal injection.

In biochemical assays, the serum levels of BUN were significantly elevated at 6 h (p < 0.001), 1 day (p < 0.05) and 3 days (p < 0.001) after injection in cisplatin treated mice (6 mg/kg, single dose, i.p.). On the other hand, the serum levels of BUN were slightly elevated at 6 h (p < 0.01) only in K101 treated mice (8.2 mg/kg, single dose, i.p.), and were significantly raised at 6 h, 1 and 3 days (p < 0.05) after injection in K102 treated mice (6.2 mg/kg, single dose, i.p.). The higher serum BUN level in K102 treated mice is considered that K102 possesses more lipophilic fluoro group than acetyl group in K101. The values of creatinine and uric acid were similar in all groups. The ultrastructural morphological changes of K101- or K102-administrated mice were less remarkable than cisplatin-administrated mice. In acid phosphatase enzyme histochemistry, cisplatin treatment induced relevant changes in the distribution pattern of enzyme activity compared with K101 or K102 treatment at 7 days after injection.

In conclusion, these results show that K101 is less nephrotoxic than cisplatin and a promising new platinum complex.

R1R2PhCCO2(CH2)2NR4R5 (I) and R1R2PhCCO2ZNR4R5 (II) were prepared by: (A) refluxing 9 hr 38 millimoles R1R2PhCCO2Na, 38 millimoles R4,R6-disubstituted chloroalkylamine-HCl, and 38 millimoles Na2CO3 in 200 ml AcOEt; (B) treating 15 millimoles R1R2PhCCO2H in 10 ml iso-PrOH at 5° with 15 millimoles R4,R5-disubstituted chloroalkylamine in 5 ml iso-PrOH and refluxing 3 hr; (C) treating 76 millimoles R4,R5-disubstituted aminoalkanol in 60 ml C6H6 with 65 millimoles R1R2PhCCOCl in 100 ml C6H6 and refluxing the mixture 4 hr.I and II prepared were (compound, R1, R2, R4, R5, Z, % yield, b.p./mm base, and m.p. HCl salt given): I, Ph, OEt, Me, Ph(CH2)2, - , 20.5, - , 170-1° (EtOH); I, Ph, OEt, Me, PhCH2, - , 48.7, 220-4°/0.6, - ; I, Ph, OCH2CH:CH2, Me, Me, - , 74.5, - , 172-3° (EtOH); I, C6H11, Me, Me, Me, - , 35, - , 147-8° (Me2CO); I, C6H11, Me, Et, Et, - , 30.8, - , 114-15° (as citrate-H2O) (Me2CO); I, Ph, Me, Me, PhCH2CH2, - , 46.1, - , 154-5°; II, Ph, OEt, Me, Me, CHMeCH2, 47.4, 143-6°/0.5, - ; II, Ph, OEt, Me, Me, CH2CHMe, 72.3, 155-8°/0.5, - ; II, Ph, OEt, Et, Et, (CH2)3, 74.4, - , 152-3° (EtOH); II, Ph, Me, Et, Et, CHMeCH2, 69.3, - , 158-61° (Me2CO); II, Ph, Me, Et, Et, CHMe(CH2)2, 98.5, - , 166-0° (AcCH2CO2Et); II, Ph, Me, Me, Me, CHMe(CH2)2, 56, - , 127-4° (EtOH); II, Ph, Me, Et, Et, CHMeCHMeCH2, 34, - , 93-5° (EtOH).Data were given for LD50 on i.p. administration to mice, peripheral and central cholinolytic activity in rabbits and cats, the min. dose decreasing the pain threshold in mice, and the min. dose inhibiting 3 min the cough reflex on stimulation of the superior laryngeal nerve in cats.