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.

The 7-substituted 6H-pyrazolo[4,5,1-de]acridin-6-ones with (aminoalkyl)amino and/or (hydroxyalkyl)amino groups in the side chains were synthesized by bromination using N-bromosuccinimide and the subsequent reaction with amines from the 7-substituted 5-bromo-2-methyl-6H-pyrazolo-[4,5,1-de]acridin-6-one. The substitution reaction of the amines with alkyl bromide (the C2 position) and aryl bromide (the C5 position) was accomplished by choosing the proper reaction conditions. These compounds show DNA intercalating ability in ethidium fluorescence assay and antiproliferative activity against Hela S3 cells. Impressive antitumor activity in vivo against murine P388 leukemia and murine sarcoma 180 solid tumor in mice was demonstrated for the 7-hydroxy analogs. In addition, some of these showed excellent antitumor activity against adriamycin-resistant murine P388 leukemia (P388/ADM) in mice.

6H-Pyrazolo(4,5,1-de)acridin-6-ones as a Novel Class of Antitumor Agents. Synthesis and Biological Activity.-The title compounds (V) and (IX) (13 derivatives) are obtained by simultaneous introduction of the same amine side chain or by substitution with different amines successively at the C-2 and C-5 positions in (II) or (VI). They show DNA intercalating ability, antiproliferative activity in vitro against Hela S3 cells and significant antitumor activity in vivo against P388 leukemia and sarcoma 180 solid tumor in mice comparable to adriamycin. In part, they are also active against adriamycin-resistant P388 leukemia. The influence of the C-7 hydroxy group and different amine functions on the activity is discussed.-(SUGAYA, T.; MIMURA, Y.; SHIDA, Y.; OSAWA, Y.; MATSUKUMA, I.; IKEDA, S.; AKINAGA, S.; MORIMOTO, M.; ASHIZAWA, T.; OKABE, M.; OHNO, H.; GOMI, K.; KASAI, M.; J. Med.

A new concept, “Radiation-Induced Drug (RID)”, was proposed as a novel type of drugs for cancer therapy. To test the usefulness of this concept, 5-fluorouracil (5-FU) derivatives having various types of substituents at the 1-position were prepared and the γ-radiolyses of their aqueous solutions were studied. The compounds having sulfonyl and thioureido groups as the substituents produced efficiently 5-FU with high G values upon γ-irradiation. The medium effects on the radiolyses revealed that the above two substituents were removed mainly with HO· and hydrated electrons eeq−.

Seventeen compounds having a variety of substituents at the 3‐ and 5′‐positions of 2′‐deoxy‐5‐fluorouridine (5‐FUdR) and 5‐fluorouridine (5‐FUR) were synthesized, and their γ‐radiolysis in aqueous solutions were studied. The compounds having thioureido (RNHCSNH, R  H, PhCH2, acyl) and thiocarbonylamino (XCSNH, X  PhCH2S, PhO) groups at the 3‐position of 5‐FUdR were efficiently cleaved to give 5‐FUdR with high G values upon γ‐irradiation of their aqueous solutions. The active species for these cleavage reactions were hydrated electron (e− aq), H• and HO•. However, the compounds having a dimethylsulfoxyimino group at 3‐position of 5‐FUdR and 5‐FUR afforded 5‐FUdR and 5‐FUR only under the radiolysis conditions where e− aq becomes a principal active species. The compound having a 2‐benzoylthiazoylthiocarbonylamino group at the 3‐position of 5‐FUdR showed the highest reactivity toward HO.. The mechanisms of these γ‐radiolysis reactions are discussed. The examination of anticellular activities of γ‐irradiated compounds having a thiocarbonylamino group at the 3‐position of 5‐FUdR toward murine Sarcoma 180 cells revealed that these compounds may be utilized as a candidate for a radiation‐induced drug (RID).