Five 1-beta-D-arabinofuranosylcytosine conjugates and two cytidine conjugates of thioether lipids (1-S-alkylthioglycerols) linked by a pyrophosphate diester bond have been prepared and their antitumor activity against an ara-C2 sensitive (L1210/0) and two ara-C resistant L1210 lymphoid leukemia sublines in mice were evaluated. These prodrugs of ara-C include ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (8a), ara-CDP-rac-1-S-octadecyl-2-O-palmitoylthioglycerol (8b), and ara-CDP-rac-1-S-octadecyl-2-O-methyl(or -ethyl, -hexadecyl)thioglycerols (8c-e). The cytidine conjugates include CDP-rac-1-S-octadecyl-2-O-palmitoyl(or -methyl)- 1-thioglycerols (9a and 9b). Sonicated solutions of the conjugates existed in the form of micellar disks (size 0.01-0.04 microns). Single doses (200-400 mg/kg) of 8a and 8b produced significant increase in life span (257-371%) in mice bearing ip implanted L1210/0 leukemia. In contrast, conjugates 8c-e were less effective (ILS 19-75%) and cytidine conjugates (9a and 9b) were ineffective. Even though 8a and 8b were found to be curative in a high percentage of mice bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C(I)], they were completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C(II)]. However, the present results, together with the previous, demonstrate that 8a and 8b are promising new prodrugs of ara-C with improved efficacy.
Three new 1-beta-D-arabinofuranosylcytosine conjugates of ether lipids (alkyl glycerols) linked by a pyrophosphate diester bond have been prepared and evaluated against mouse leukemia L1210 and P388. These include ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (9a) (ara-CDP = 1-beta-D-arabinofuranosylcytosine 5'-diphosphate), ara-CDP-rac-1-O-octadecyl-2-O-palmitoylglycerol (9b), and ara-CDP-rac-1-O-octadecyl-2-O-methylglycerol (9c). Among them, conjugate 9a produced significant increase in life span (200-293%) in mice bearing ip and ic implanted L1210 lymphoic leukemia at a total dose of 400-500 mg (406-508 mumol/kg). Significant schedule dependence was not observed when the conjugate was given ip once daily on day 1, days 1, 5, and 9, and days 1-5. The new conjugates are water soluble by sonication.
The L-, D-, and D,L-isomers of 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitin, new prodrugs of ara-C5, have been evaluated for antitumor activity in L1210 lymphoid leukemic mice. The L-isomer produced significant increase in life span (ILS), and longterm survivors among mice bearing i.p. and i.c. implanted L1210 leukemia and the maximal ILS values found were greater than 543 and greater than 374% with five and four 45-day survivors out of six mice, respectively, at the optimal single doses of 300 mg/kg and 125 mg/kg. The D- and D,L-isomers also displayed significant in vivo antitumor activity against both i.p. and i.c. implanted L1210 leukemia in mice with ILS range of 144-293% at a total dose of 125-250 mg/kg. Significant schedule dependency was not observed when the conjugates were administered i.p. once daily for 5 days, once every 4 days, or as a single dose, but single doses typically produced the best effects. The L-isomer was found to be a more effective prodrug of ara-C than its isomers and other lipophilic prodrugs, 5'-O-palmitoyl-ara-C and N4-acyl-ara-C. Unlike the latter prodrugs, the new conjugates are water soluble by sonication method.
Five new P1-(steroid-21-yl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyro phosphates (ara-CDP-steroids), five 1-beta-D-arabinofuranosylcytosine 5'-O-(alkyl)phosphates (ara-CMP-alkyl esters), and two P1-(alkyl)-P2-(1-beta-D-arabinofuranosylcytosin-5'-yl)pyrophosphat e (ara-CDP-alkyl esters) have been prepared and evaluated against L1210 lymphoid leukemia in culture and in mice (C3D2F1/J). These include ara-CDP-11-deoxycorticosterone (6a), ara-CDP-cortisone (6c), ara-CDP-corticosterone (6d), ara-CDP-cortexolone (6e), and ara-CDP-prednisone (6g), ara-CMP hexadecyl ester (7a), ara-CMP 1-cyclohexylmethyl ester (7b), ara-CMP 1-adamantylmethyl ester (7c), ara-CMP 2-(1-adamanthyl)ethyl ester (7d), ara-CMP 2-chloroethyl ester (7e), ara-CDP hexadecyl ester (9a), and ara-CDP 1-cyclohexylmethyl ester (9b). The in vitro antitumor results indicated that ara-CDP-steroids were as active as the previously reported ara-CMP-steroids and that ara-CMP and ara-CDP-alkyl esters were less growth inhibiting than ara-CDP-steroids and ara-C. However, the in vivo antitumor results indicated that ara-CDP-steroids were generally less effective than the previous monophosphate derivatives. Among them ara-CDP-corticosterone (6d) and the known ara-CDP-cortisol (6b) showed greater efficacy than ara-C with ILS value of 152% and 209%, respectively, at the optimal dose of 40 and 80 (mg/kg)/day for 9 days, while that of ara-C was 138% at the optimum dose of 9.2 (mg/kg)/day. Generally, ara-CMP alkyl esters (7a-e), given ip to the L1210 leukemic mice, were found to be toxic and ineffective. However, ara-CDP hexadecyl ester (9a) showed marginal activity (ILS, 38%). These preliminary results support the thesis that the ara-C conjugates of this type may require a lipophilic and naturally occurring moiety for improved efficacy.
Three 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitins from L-, D-, and DL-alpha-dipalmitoylphosphatidic acids have been synthesized and their antitumor activity against two ara-C2 resistant L1210 lymphoid leukemia sublines in mice were evaluated. These new prodrugs of ara-C include ara-CDP-L-dipalmitin, ara-CDP-D-dipalmitin, and ara-CDP-DL-dipalmitin. The L and DL isomers produced significant increase in life span (greater than 400%) and four to five long-term survivors (greater than 45 days) out of six animals bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C (I)], while the D isomer displayed a marginal activity (ILS 100-121%). In contrast, the L isomer was completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C (II)]. However, the results demonstrate that the L and DL isomers of ara-CDP-dipalmitin are promising new prodrugs of ara-C with improved efficacy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.