Synthesis, antitumor activity, and chemical properties of silaplatin and related platinum(II) and platinum(IV) complexes derived from .beta.-silyl amines

Abstract

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.

A Short and Efficient Enantiomeric Synthesis of Antitumor Fused Tetrahydrofurans

“…[5a] It is exceptional to find examples of silicon-containing anticancer drugs in the literature. However, cisplatin [16] and camptothecin [17] analogs containing silicon have been reported to give better activity profiles than their respective parent drugs.…”

New C-functionalized silacycloalkanes (CH2)nSi(CH2X)2 and (CH2)nSi(CH2X)CH2X′ (n = 3, 4; X, X′ = functional group): Synthesis and reactivity studies of analogous silacyclobutanes and silacyclopentanes

“…Different synthetic methods for this transformation were applied (Scheme 4) using various reaction conditions, but in all cases SieCH 2 NH 2 bond cleavage was observed. The sensitivity of the SieCH 2 NH 2 group against nucleophiles has already been reported for some related (aminomethyl)silanes 3,9 ; however, this reactivity profile is not yet fully understood. All attempts to synthesize the corresponding silacyclobutane derivative 4b also failed.…”

“…3 Compound 4a was obtained by treatment of 1a with sodium azide and subsequent reaction of the resulting 1,1-bis(azidomethyl)-1-silacyclopentane with lithium aluminum hydride. As multifunctional (azidomethyl) silanes can be hazardous explosives, 3,8 an alternative synthetic route for the preparation of 4a and its derivative 1,1-bis(aminomethyl)-1-silacyclobutane (4b) was studied by using the Gabriel synthesis (Scheme 4). Thus, treatment of 1a with potassium phthalimide and 18-crown-6 in N,N-dimethylformamide yielded 1,1-bis(phthalimidomethyl)-1-silacyclopentane (13a) (77% yield), which, however, could not be converted into the corresponding diamine 4a.…”

Silyl modification of biologically active compounds. 13. Synthesis, cytotoxicity and antibacterial action of N‐methyl‐N‐(2‐triorganylsiloxyethyl)‐1,2,3,4‐tetrahydro(iso)quinolinium iodides

“…This strategy has been successfully applied in the antitumour drug analogues silatecans (silicon-containing camptothecins) [1,2] and silaplatins (cisplatin analogues), [3] the HIV-1 reverse transcriptase inhibitor TSAO-T [4] and the effective anabolic 'silabolin'. This strategy has been successfully applied in the antitumour drug analogues silatecans (silicon-containing camptothecins) [1,2] and silaplatins (cisplatin analogues), [3] the HIV-1 reverse transcriptase inhibitor TSAO-T [4] and the effective anabolic 'silabolin'.…”