Nucleoside conjugates. 7. Synthesis and antitumor activity of 1-.beta.-D-arabinofuranosylcytosine conjugates of ether lipids

Abstract

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.

Synthesis of sulfur-containing glycerophospholipids

“…60% yield, although acyl migration remained an issue [43]. Substituted glycerols 5c-g were phosphorylated with POCl 3 and Et 3 N [45] to form acids 17 [43].…”

“…Several studies [43,45,48,49] have reached the general conclusion that a thioether at the sn-1 position and an sn-2 fatty acyl chain can improve the antitumor activity of lipids, suggesting that compounds such as those in scheme 4 hold potential as pro-drugs of ara-C. The chemistry of pyrophosphate-linked sulfur-containing lipids also encompasses some anti-HIV nucleoside conjugates [27].…”

“…The chemistry of pyrophosphate-linked sulfur-containing lipids also encompasses some anti-HIV nucleoside conjugates [27]. Linkage of (±)-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol 3-phosphate (17f) to nucleoside 5 -monophosphoromorpholidates by established protocols [43,45] afforded conjugates 20-22f [27]. Acting as pro-drugs, compounds 20f and 21f delivered AZT (3 -azido-3 -deoxythymidine) and AzddU (3 -azido-2 ,3 -dideoxyuridine), Downloaded by [The University of Manchester Library] at 02: 25 12 October 2014 SCHEME 4 respectively, and exhibited longer half-lives than when administered by a direct introduction method [27].…”

Lipid Nucleoside Conjugates for the Treatment of Cancer

“…With this consideration in mind, Hong et al synthesized oxyether phospholipids with different chain lengths and attached them to ara-C [64]. The most significant finding was the use of the compound seen in Fig.…”

“…implanted tumors are demonstrating the ability of these conjugates to cross the blood-brain barrier. Hong et al conclude from their results that among possible explanations for why these conjugates are more biologically active compared to ara-C alone include the following: (1) resistance to hydrolysis by cytidine deaminase, (2) rapid interaction with serum lipoproteins (better plasma transport), (3) rapid uptake by cells, (4) effects on lipid biosynthesis, and (5) hydrolysis of the conjugates to release ara-CMP [64]. Lastly, the carrier molecules themselves may have antitumor effects after the conjugates are hydrolyzed in the cytoplasm.…”