US EPA

7433126 

Journal Article 

Synthesis and antileukemic activity of 5-substituted 2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine diesters 

Anderson, WK; Corey, PF; , 

1977 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

AMER CHEMICAL SOC 

WASHINGTON 

20 

6 

812-818 

English 

874955 

10.1021/jm00216a014 

WOS:A1977DG77700014 

https://pubs.acs.org/doi/abs/10.1021/jm00216a014
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Treatment of N-acylproline derivatives, 2, with acetic anhydride--dimethyl acetylenedicarboxylate (DMAD) gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate (5). The reaction proceeds via a 1,3-dipolar addition of DMAD with the mesoionic oxazalone intermediate 3, generated in situ, with concomitant elimination of carbon dioxide. Reduction of 5 gave the diols 6 which upon subsequent acylation gave 1. The bis(N-methylcarbamate) 1d and the diacetate li show a modest level of in vivo antileukemia activity in the L1210 assay. A majority of the diesters, 1, showed significant antileukemic activity in the in vivo P-388 assay. The bis(carbamate) 1d afforded "cures" at dose levels as low as 12.5 mg/kg; 1 q showed potent activity at doses as low as 0.78 mg/kg. Several other compounds showed potent activity against P-388 over a greater than fourfold dose range with no acute toxicity. Half-lives for several diacetate derivatives of 1 were determined for aqueous Me2SO solutions. The preparation of 7 and 8 shows that 1 may react by O-alkyl ester cleavage. 

pyrrolidine derivative; 2,3 dihydro 6,7 bis(hydroxymethyl) 5 phenyl 1h pyrrolizidine dicarbamate; 5 (3,4 dichlorophenyl) 2,3 dihydro 1h pyrrolizine 6,7 dicarboxylic acid dimethyl ester; 6,7 bis(n alkylcarbamoylmethyl) 2,3 dihydro 1h pyrrolidine; cytotoxicity; dose response; drug analysis; drug comparison; drug identification; drug response; drug screening; drug synthesis; drug toxicity; in vitro study; infrared spectrometry; intraperitoneal drug administration; leukemia; mouse; nuclear magnetic resonance spectroscopy; theoretical study; Animal; Antineoplastic Agents; Cell Survival; Comparative Study; Female; In Vitro; Leukemia L1210; Leukemia, Experimental; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred Strains; Pyrroles; Structure-Activity Relationship; Support, U.S. Gov't, P.H.S.