Synthesis and biological activity of novel mitomycin C analogs derived from mitomycin A

Abstract

A variety of mitomycin C analogs were synthesized from mitomycin A and their biological activities were studied. Mitomycin A (1) underwent nucleophilic displacement reactions involving intramolecular hydrogen migrations upon treatment with nitrogen nucleophiles bearing mobile hydrogens, but the mode of hydrogen migration depended on the nature of the nucleophiles. The reaction with alkoxyamines gave compounds 6 and 7 which have the 5H‐6‐alkoxyimino‐4,7‐dione structure in ring A of 1. However, the reaction with hydroxylamine and benzoylhydrazine afforded compounds 11 and 13 which have the 4‐hydroxy‐6‐hydroxyimino‐7‐one structure and the 4‐hydroxy‐6‐hydrazono‐7‐one structure, respectively, in ring A of 1. These products were converted into various types of mitomycin C derivatives by methylation with methyl iodide or dimethyl sulfate. The mechanistic features of these reactions are discussed. The in vitro and in vivo biological activities were tested by using P388 leukemia and Sarcoma 180 tumor cells. Several of the synthesized compounds exhibited better activity than that of mitomycin C.

N,N-Diisopropyl-N-phosphonyl imines lead to efficient asymmetric synthesis of aziridine-2-carboxylic esters

“…1 One of the privileged substructures among the nitrogen-containing heterocycles is represented by the aziridine ring which has been found in a variety of biologically active natural products including mitomycin, azicemycin, azinomycin and maduropeptin. 2a,2b The structure-activity relationship (SAR) studies on mitosane derivatives revealed that the aziridine ring is crucial for their antitumor activity and selectivity. 2c–2f This study has led to the finding that mitomycin C can act as the most potent candidate possessing antitumor activities against stomach, breast, oesophagus and bladder tumors.…”

“…2a,2b The structure-activity relationship (SAR) studies on mitosane derivatives revealed that the aziridine ring is crucial for their antitumor activity and selectivity. 2c–2f This study has led to the finding that mitomycin C can act as the most potent candidate possessing antitumor activities against stomach, breast, oesophagus and bladder tumors. 2b Many other aziridine-containing derivatives have also been found to exhibit various biological properties.…”

“…2c–2f This study has led to the finding that mitomycin C can act as the most potent candidate possessing antitumor activities against stomach, breast, oesophagus and bladder tumors. 2b Many other aziridine-containing derivatives have also been found to exhibit various biological properties. 2a,3a,3b For example, 2-(4-amino-4-carboxybutyl)aziridine-2-carboxylic acid 1 can serve as a potent irreversible inhibitor of the bacterial enzyme diaminopimelic acid epimerase while 2-(2- carboxyethyl)aziridine-2-carboxylic acid 2 as an irreversible inhibitor of glutamate racemase (Fig.…”

“…1). 2a,3a,3b One of the major reasons for aziridines to play an important role in chemical and biomedical sciences is based on the fact that the strained three-membered rings can undergo regio- and stereoselective ring opening reactions. 4a,4b For example, the aziridine-2-carboxylic esters can serve as versatile building blocks for making α- and β-amino acids, β-substituted α-amino acids, β-hydroxy α-amino acids, α-amino aldehydes and ketones.…”