Synthesis and biological evaluation of purine-containing butenolides.
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.
Hakimelahi
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GH
Institute of Chemistry, Academia Sinica, Taipei, Taiwan 115, Republic of China. hosein@chem.sinica.edu.tw
Mei
N W
NW
Moosavi-Movahedi
A A
AA
Davari
H
H
Hakimelahi
S
S
King
K Y
KY
Hwu
J R
JR
Wen
Y S
YS
D015107:4-Butyrolactone / Q000031:analogs & derivatives; D043383:Adenosylhomocysteinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000172:deficiency; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D005663:Furans; D011687:Purines; C004511:butenolide; D013937:Thymidine Kinase; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D015107:4-Butyrolactone