Benzothiopyranoindazoles, a new class of chromophore modified anthracenedione anticancer agents. Synthesis and activity against murine leukemias

• Published in: Journal of medicinal chemistry Vol. 31; no. 8; pp. 1527 - 1539
• Main Authors: Showalter, H. D. Hollis, Angelo, Mario M, Berman, Ellen M, Kanter, Gerald D, Ortwine, Daniel F, Ross-Kesten, Suzanne G, Sercel, Anthony D, Turner, William R, Werbel, Leslie M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-08-1988
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Chemical Phenomena; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; In Vitro Techniques; Indazoles - chemical synthesis; Indazoles - pharmacology; Indazoles - therapeutic use; Leukemia L1210 - drug therapy; Leukemia P388 - drug therapy; Mice; Organic chemistry; Preparations and properties; Pyrazoles - chemical synthesis; Structure-Activity Relationship; Antineoplastic agent; Diamine; Sulfur nitrogen heterocycle; In vivo; P388»-Leukemia; Aromatic compound; L1210-Leukemia; Tetracyclic compound; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00403a009

The synthesis of the benzothiopyranoindazoles, a new class of chromophore modified anthracenediones related to mitoxantrone, is described. In this structural class the quinone moiety, which is believed to be responsible for the cardiotoxicity of the anthracyclines, has been designed out. The synthesis of the benzothiopyranoindazoles was carried out by a multistep sequence from requisite 1-chloro-4-nitro-9H-thioxanthen-9-one precursors. Reaction with a monoalkylhydrazine gave a 5-nitrobenzothiopyranoindazole adduct, which was catalytically reduced to a corresponding C-5 anilino intermediate. Alkylation of 7 with a requisite X(CH2)nNR1R2 (X = Cl, Br; R1, R2 = H, alkyl, acyl; n = 2,3) provided target "two-armed" benzothiopyranoindazoles or A-ring methoxy and/or side chain acyl intermediates, which could be converted to 3 by appropriate deprotection methodologies. Alternatively, certain target compounds 3 were synthesized by reaction of 7 with appropriately functionalized glycine precursors under Schotten-Bauman or BOP chloride condensation conditions to provide C-5 acylamino intermediates, followed by Red-Al reduction and deprotection steps. Described also is the synthesis of selected benzothiopyranoindazole congeners with proximal acylamino side chains at C-5 and B-ring sulfone functionality at S-6. Potent activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-9) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by (a) a basic side chain at N-2 and a dibasic side chain at C-5 with primary or secondary distal amine substitution, (b) certain patterns of A-ring hydroxylation with 8-OH and 9-OH most favorable, and (c) sulfide oxidation state at S-6. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional broad-spectrum in vivo anticancer activity, selected compounds in this series have been chosen for development toward clinical trials.