Hybrid anticancer 1,2-diazine derivatives with multiple mechanism of action. Part 3.
Antitumour chemotherapy is nowadays a very active field of research, DNA targeting drugs being the most widely used group in therapy. The design, synthesis and anticancer activity of a new class of anticancer derivatives with pyrrolo-1,2-diazine and benzoquinone skeleton is presented. The synthesis is direct and efficient, involving an alkylation followed by a [3+2] dipolar cycloaddition. The penta- and tetra-cyclic pyrrolo-1,2-diazine were evaluated for their in vitro anticancer activity against an NCI 60 human tumour cell line panel. The pentacyclic-1,2-diazine exhibit a significant anticancer activity against Non-Small Cell Lung Cancer NCI-H460, Leukemia MOLT-4, Leukemia CCRF-CEM and Breast Cancer MCF7. We hypothesize that these molecules will exert their anticancer activity through multiple mechanisms of action: intercalating the DNA, inhibiting the topoisomerase enzymes and, destroying the DNA strands via electron transfer mechanism. However, the intercalation with the DNA seems to prevail in competition with the others mechanisms.
"Al. I. Cuza" University of Iasi, Faculty of Chemistry, Research Department, Bd. Carol 11, 700506 Iasi, Romania.
Vasilichia
V
Antoci
"Al. I. Cuza" University of Iasi, Organic and Biochemistry Department, Bd. Carol 11, 700506 Iasi, Romania.
Dorina
D
Mantu
"Al. I. Cuza" University of Iasi, Organic and Biochemistry Department, Bd. Carol 11, 700506 Iasi, Romania.
Danut Gabriel
DG
Cozma
"Apollonia" University of Iasi, Faculty of Dentistry, Str. Păcurari 11, 700511 Iasi, Romania.
Cornelia
C
Usru
"Al. I. Cuza" University of Iasi, Organic and Biochemistry Department, Bd. Carol 11, 700506 Iasi, Romania. Electronic address: ionelm@uaic.ro.
Ionel I
II
Mangalagiu
D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011724:Pyridazines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D059003:Topoisomerase Inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D016227:Benzoquinones; D011724:Pyridazines; D011758:Pyrroles; C508945:Pyrrolopyridazine; D059003:Topoisomerase Inhibitors; C004532:quinone; D004247:DNA