Radioprotective stereostructure-activity study of cis- and trans-2-mercaptocyclobutylamine analogs and homologs of 2-mercaptoethylamine

Abstract

For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for MEA, cis- and trans-2-mercaptocyclobutylamine (2), cis- and trans-2-mercaptocyclobutylmethylamine (3), and trans-2-mercaptomethylcyclobutylamine (4) are discussed in terms of their ability to chemically reduce transient free radicals, the formation of single strand breaks in DNA, and protect Chinese hamster cells (in vitro) and mice against the lethal effects of ionizing radiation. The results are interpreted in light of current proposed mechanisms of action for MEA. No correlation exists between ability of these analogs to enhance mice survival times and their ability to protect against the induction of DNA single strand breaks and the inactivation of proliferative capacity of hamster cells growing in vitro. Analysis of two isomers (cis- and trans-3) on the repair of single strand breaks showed both isomers only marginally influenced the rate and did not influence of extent of single strand break rejoining. The results are consistent with a mode of action involving chemical repair of transient radicals and protection against DNA and critical enzymatic sites.

Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes

“…This approach might not always be justifiable at the later drug development phases (i.e., industrial route scouting) but can be very useful in the early discovery stages (i.e., hit-to-lead or lead optimization) when a series of structurally similar derivatives are needed. Therefore, we did not rely on the previous approaches to compounds 1 , 2 , − 3 , and 10 . Instead, our strategy was based on using structurally related starting materials 14 – 17 accessible to us in large quantities.…”

“…Therefore, we did not rely on the previous approaches to compounds 1, 49 2, 50−52 3, 53 and 10. 54 Instead, our strategy was based on using structurally related starting materials 14−17 accessible to us in large quantities. These compounds can be easily prepared via [2 + 2] cycloaddition of 1,1-dimethoxyethene and the corresponding Michael acceptors (for compound 15, we used a modified protocol described in the Experimental Section), 25,55 acyloin-type cyclization of dimethyl succinate, 56 or bromination of cyclobutanone 57,58 (Scheme 1).…”

Thermal Isomerizations of 2-d-1-(E)-Propenylcyclobutanes to 4-d-3-Methylcyclohexenes

“…The synthetic prerequisites posed by this projected investigation have been addressed successfully through a reaction sequence starting with racemic trans -1,2-cyclobutanedicarboxylic acid. Its monoethyl ester acid chloride was reduced using n -Bu 3 SnD and (Ph 3 P) 4 Pd); the deuterioaldehyde formed was decarbonylated to give ethyl trans -2- d -cyclobutanecarboxylate. Utilizing a stereochemically controlled Horner−Wittig protocol, the d -labeled ester was converted to a 1:1 mixture of crystalline diastereomeric syn -2-diphenylphosphinoyl-1-cyclobutylpropane-1-ols ( 2 H NMR δ 1.89 and 1.66).…”