Pyrrolo[2,1-d][1,2,3,5]tetrazine-4(3H)-ones, a new class of azolotetrazines with potent antitumor activity.
Pyrrolo[2,1-d][1,2,3,5]tetrazinones 10a-o, compounds that hold the deaza skeleton of the antitumor drug temozolomide, were prepared by reaction of 2-diazopyrroles 9 and isocyanates. Such a synthetic route represents, among those leading to azolotetrazinones reported so far, the only possible one since attempts to cyclize to the title ring system 2-amino-1-carbamoylpyrroles 11 or the mono substituted 2-triazenopyrrole 12 failed. Compounds 10 were screened at the National Cancer Institute (NCI) for their activity against a panel of about 60 human tumor cell lines. Most of them possess remarkable antineoplastic activity having GI(50) values in the low micromolar or sub-micromolar range and reaching, in the case of compound 10d, nanomolar concentrations. The most sensitive cell lines were MDA-N and MDA-MB-435 of the breast sub-panel, and SR, K-562, HL60 (TB) and CCRF-CEM of the leukaemia sub-panel. SAR evaluation and COMPARE computations indicate, for compounds 10, a mechanism of action different from that of temozolomide.
Dipartimento Farmacochimico Tossicologico e Biologico, Università degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy.
Patrizia
P
Diana
Paola
P
Barraja
Antonino
A
Lauria
Alessandra
A
Montalbano
Anna Maria
AM
Almerico
Gaetano
G
Dattolo
Girolamo
G
Cirrincione
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017953:Isocyanates / Q000737:chemistry; D020014:K562 Cells; D051379:Mice; D009588:Nitrogen Mustard Compounds; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007093:Imidazoles; D017953:Isocyanates; D009588:Nitrogen Mustard Compounds; D011758:Pyrroles; C040369:mitozolomide