Synthesis and biological activity of several aminonucleoside-platinum(II) complexes

Abstract

Several platinum(II) complexes of 3',5'-diamino-3',5'-dideoxythymidine (compound 1), 5'-amino-5'-deoxythymidine (compound 2), and 3'-amino-3'-deoxythymidine (compound 3) and the respective 2'-deoxyuridine amino nucleoside complexes, 4-6, have been synthesized. Whereas compounds 1, 2, and 4-6 had no inhibitory effect on the replication of murine L1210 cells in cell culture, compound 3 [(3'-AdThd)2PtCl2] inhibited these cells with an ED50 of 0.8 microM. Incubation of L1210 cells with 10-20 microM compound 3 for 2 h produced less than 18% inhibition of RNA, DNA, or protein synthesis, which is of questionable significance. However a 16-h incubation resulted in an increased uptake of labeled thymidine into DNA (77%), labeled uridine into RNA (17%), and labeled amino acids into protein (100%). These unexpected results indicate that inhibition of macromolecules may not be involved in the inhibition of the replication of L1210 cells. The increased incorporation of labeled metabolites into macromolecules may be related to the increase in cell volume after a 2-h incubation of L1210 cells with compound 3 plus a marked increase after 2 h in the proportion of cells in their S phase. Compound 3 appears to delay the progression of cells through their cell cycle. A marked inhibitory effect on the transport of methionine or aminoisobutyric acid into L1210 cells was found with compound 3, which was slightly greater than that produced with cisplatin. Compound 3 had a dose-dependent effect on the survival of mice bearing the L1210 ascites neoplasm, with a T/C X 100 of 175 at a dose of 320 mg/kg. Investigation of the kinetics of decomposition in aqueous systems demonstrated that the primary UV-absorbing decomposition product is 3'-amino-3'-deoxythymidine and that only a limited amount of the compound is formed (less than 8%). Although 3'-amino-3'-deoxythymidine could account for a part of the inhibition of the replication of L1210 cells in culture, it cannot account for the inhibition of amino acid transport by compound 3, the platinum complex of 3'-amino-3'-deoxythymidine. Compound 3 has been shown to limit part of the amino acid uptake into L1210 cells in a similar manner to cisplatin.

Mitochondrial Mode of Action of a Thymidine‐Based Cisplatin Analogue Breaks Resistance in Cancer Cells

“…cis ‐Dichloro(3′,5′‐diamino‐3′,5′‐dideoxy‐ D ‐ erythro ‐thymidine)‐platinum(II) (5) :17 With ligand 2 and K 2 [PtCl 4 ] (259.15 mg, 0.624 mmol); yield 297 mg (94 %); 1 H NMR (400 MHz, [D 6 ]DMSO): δ = 11.33 (s, 1 H; NH), 7.45 (s, 1 H; H‐6), 6.22–5.04 (m, 5 H; H‐1’, NH 2 ), 3.62–3.40 (m, 2 H; H‐3, H‐4), 2.78–2.14 (m, 4 H; H‐5′, H‐5′′, H‐2, H‐2′), 1.80 ppm (s, 3 H; CH 3 ); 13 C NMR (100 MHz, [D 6 ]DMSO): δ = 163.71 (C‐4), 150.14 (C‐2), 136.7 (C‐6), 110.1 (C‐5), 83.6 (C‐4′), 80.1 (C‐1′), 55.9 (C‐3′), 44.9 (C‐5′), 35.9 (C‐2′), 11.9 (CH 3 ); IR (ATR): $\tilde \nu $ max =3478, 3194, 3114, 2825, 1659, 1470, 1368, 1268, 1209, 1076, 1030, 952, 770, 697 cm −1 ; MS (micro‐ESI): m/z : 529.1 [ M +Na] + , 544.1 [ M +K] + ; elemental analysis calcd (%) for C 10 H 16 Cl 2 N 4 O 3 Pt: C 23.73, H 3.19, N 11.07; found: C 22.75, H 3.57, N 10.18.…”

“…Among them, a dose dependent increase in survival time in mice bearing the L1210 tumor was only observed for the dichlorobis(3'-amino-3'-deoxy-d-erythro-thymidine)-platinum(II) complex. [17] Although the mode of action could not be assigned clearly, it has been assumed that the kind of nucleobase and sugar unit has a strong influence on the antiproliferative activity of the corresponding complexes. Inspired by the strong dependency of biological activity on the configuration of diaminosaccharides and -nucleosides attached to metal ions, [11,17] the respective d-threo configured derivative of thymidine with a pseudo-axial arrangement of the amino group in the 3'-position was used to coordinate platiA C H T U N G T R E N N U N G num(II) in the present study.…”

“…Inspired by the strong dependency of biological activity on the configuration of diaminosaccharides and -nucleosides attached to metal ions, [11,17] the respective d-threo configured derivative of thymidine with a pseudo-axial arrangement of the amino group in the 3'-position was used to coordinate platiA C H T U N G T R E N N U N G num(II) in the present study. For comparison, the analogue d-erythro derivative [17] as well as the palladium complexes were also synthesized and tested for their antitumor activity in vitro.…”

“…All compounds studied so far have possessed the D ‐erythro configuration. Among them, a dose dependent increase in survival time in mice bearing the L1210 tumor was only observed for the dichlorobis(3′‐amino‐3′‐deoxy‐ D ‐erythro ‐thymidine)‐platinum(II) complex 17. Although the mode of action could not be assigned clearly, it has been assumed that the kind of nucleobase and sugar unit has a strong influence on the antiproliferative activity of the corresponding complexes.…”

“…Although the mode of action could not be assigned clearly, it has been assumed that the kind of nucleobase and sugar unit has a strong influence on the antiproliferative activity of the corresponding complexes. Inspired by the strong dependency of biological activity on the configuration of diaminosaccharides and ‐nucleosides attached to metal ions,11, 17 the respective D ‐threo configured derivative of thymidine with a pseudo‐axial arrangement of the amino group in the 3′‐position was used to coordinate platinum(II) in the present study. For comparison, the analogue D ‐erythro derivative17 as well as the palladium complexes were also synthesized and tested for their antitumor activity in vitro.…”