1-β-D-Arabinofuranosylcytosine Conjugates of Thioether Phospholipids as a New Class of Potential Antitumor Drugs

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Abstract
Three 1-β-D-arabinofuranosylcytosine (ara-C)* conjugates of 1-S-alkyl-phospholipids (thioether phospholipids) were tested for their antitumor efficacies against L1210 and P388 leukemia in mice. These include 1-β-D-arabinofuranosylcytosine 5′-diphosphate-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (araCDP-β-palmitoyl-DL-thiochimyl alcohol, I), ara-CDP-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (ara-CDP-β-palmitoyl-DL-thiobatyl alcohol, II), and araCDP-rac-1-S-octadecyl-2-O-hexadecyl-1-thioglycerol (ara-CDP-β-cetyl-DL-thiobatyl alcohol, III). Conjugates I and II produced significant increase in life span (293-379%) and longterm survivors among mice bearing i.p. implanted L1210 lymphoid leukemia at a total dose of 400 mg (389-400 µmole)/kg. Conjugate II also displayed a strong antitumor activity against i.c. implanted L1210 leukemia in mice with an ILS range of 160-200% at a total dose of 300-450 mg (292-438 µmole)/kg. Significant schedule dependency was not observed when the conjugates were administered i.p. once daily with following schedules: qd 1; 1,5, 9; 1-5; and 1-9, but single doses typically produced the best effects. The i.p. administration of conjugate II gave the best results on survival of i.p. inoculated L1210 leukemic mice, then followed by the s.c. and i.m. treatments. The i.v. treatment produced a lower activity than the others. Conjugate II also exhibited a strong antitumor activity against i.p. implanted P388 leukemia in mice with ILS values of >255->329% with 3-5 45-day survivors at a total dose of 300-500 mg (292-486 µmole)/kg (qd 1 or 1-5). The new conjugates I and II displayed a comparable or somewhat higher activity than the previous diacyl and 1-0-alkyl analogs.

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