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Synthesis and biological evaluation of purine-containing butenolides.

Abstract：

:6-Chloropurine derivatives of gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 3a, gamma-(Z)-ethylidene-2-methoxy-3-(4-nitro)benzyloxybutenolide 3b, gamma-(Z)-ethylidene-2-(4-nitro)benzyloxy-3-methoxybutenolide 3c, gamma-(Z)-ethylidene-2,3-di(4-nitro)benzyloxybutenolide 3d, and dimethylphosphono-gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 11 as well as the adenine derivative of gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 6 were synthesized. The key steps in the high-yield synthesis of 6 involved hydration/dehydration of the C(4)=C(5) in the precursor 3a. In the presence of NH4OH at elevated temperature, 3a underwent a reverse Michael-type addition with water to produce hydrate 5. At 37 degrees C, 6 was also hydrated in the presence of S-adenosyl-L-homocysteine hydrolase to afford 5. Butenolide 6 exhibited an inhibitory property toward the enzyme. Such type II (enzyme-mediated addition of water across C(4)=C(5)) mechanism is the first example of "enzyme-substrate intermediate" inactivation of S-adenosyl-L-homocysteine hydrolase. In contrast with type I mechanism-based inactivation, reduction of enzyme-bound NADP(+) to NADPH was not observed. Upon treatment with HCl, stereoselective dehydration of 5 occurred to give the target molecule 6. At ambident temperature, 3a was hydrated in the presence of NH4OH or pig liver esterase to produce 6-chloropurine derivative 4. An unambiguous proof of the structures of 3-5 was obtained by X-ray crystallographic analysis. For the synthesis of phosphonate derivative 11, the key step involved chlorination of phosphonate 9 by use of CF3SO2Cl and 1,8-diazabicyclo[5.4.0]undec-7-ene in CH2Cl2. 6-Chloropurine-containing butenolide 3d, 6-chloropurine derivative of 4-hydroxybutenolide 4, and adenine-containing 4-hydroxybutenolide 5 did not show anticancer and antiviral activities. 6-Chloropurine-containing ethylidene-2,3-dialkoxybutenolides 3a-c and phosphonate 11, however, exhibited inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. They were also notably active toward thymidine kinase-deficient varicella-zoster virus (TK(-)VZV). Adenine-containing ethylidene-2,3-dimethoxybutenolide 6 exhibited marked selectivity in cytostatic activity against the murine leukemia (P388) cell line.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Hakimelahi GH,Mei NW,Moosavi-Movahedi AA,Davari H,Hakimelahi S,King KY,Hwu JR,Wen YS

doi

10.1021/jm0004446

keywords:

subject

Has Abstract

pub_date

2001-05-24 00:00:00

pages

1749-57

issue

eissn

0022-2623

issn

1520-4804

pii

jm0004446

journal_volume

pub_type

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Synthesis and biological evaluation of purine-containing butenolides.