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

Abstract

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.

Synthesis of bis‐pyrrole tetra esters and alcohols as novel mimetics of the anticancer mitomycin

“…Our initial attempts, analogous to the reported methods adopted for the pyrrole diesters [4, 5, 25], to reduce the tetra ester with lithium aluminum hydride (LAH) in ether or tetrahydrofuran resulted in a low yield of the desired tetra alcohol. The reaction mixture contained a variety of products, presumably owing to incomplete reduction.…”

“…Extensive studies by Anderson et al . [4–7] have shown that functionalized pyrrole and pyrrolizine derivatives [ e.g. , 1,2,5‐trisubstituted 3,4‐bis(hydroxymethyl pyrrole‐ N ‐methyl carbamate)] 4 and 5 possess potent antitumor activity in vivo analogous to that of the anticancer mitomycins and pyrrolizidine alkaloids.…”

“…, electron donating or electron withdrawing groups) on the heteroaromatic nucleus. Thus, an optimally functionalized molecule with stability in vitro and reactivity in vivo can be designed as a synthetic mimic of the anticancer alkaloids [4–7]. Indeed, the biological evaluation of a number of such derivatives has revealed compounds with potent antitumor activity in vitro and in vivo [8].…”

Core‐Structure‐Motivated Design of Iminium–Enolate Organocascade Reactions: Enantioselective Syntheses of 5,6‐Dihydroindolizines

“…The indolizine core is a privileged heterocyclic ring system found in a large number of bioactive natural alkaloids and clinically useful pharmaceuticals 2. The 5,6,7,8‐tetra‐ and 5,6‐dihydroindolizine frameworks (Figure 1) have recently drawn tremendous interest from both synthetic and medicinal chemists because of their properties as anti‐tumor,3a,g anti‐leukemia,3b anti‐cholinergic agents,2a and other important biological activities 3. In addition, 5,6,7,8‐tetra‐ and 5,6‐dihydroindolizine alkaloids are common secondary metabolites in plants, invertebrates, fungi, and bacteria 4.…”

Methyl 4-phenyl-1,2,3,3a,4,4a,5,12c-octahydronaphtho[1′,2′:3,2]furo[5,4-b]pyrrolizine-4a-carboxylate

“…For general background to pyrrolizine derivatives, see: Barsoum & Nawar (2003); Abbas et al (2010); Anderson & Corey (1977); Makoni & Sugden (1980); Laufer et al (1997). For a related structure, see: Nirmala et al (2009).…”