Synthesis and antiproliferative activity of 2,6-diamino-9-benzyl-9-deazapurine and related compounds.
Treatment of 6-bromomethyl- or 6-dibromomethyl-5-nitropyrimidine-2,4-diamine with KCN gave the same product--(2,6-diamino-5-nitropyrimidinyl)acetonitrile. Benzylation of the nitrile took place on the alpha-carbon to the cyano group preferentially affording the corresponding mono- and dibenzyl derivative, whose reductive cyclization resulted in 7-benzyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine and 7,7-dibenzyl-7H-pyrrolo[3,2-d]pyrimidine-2,4,6-triamine, respectively. Suitability of the protection of N(2) and N(4) atoms with benzyl, acetyl, or benzoyl groups was also investigated. The in vitro evaluation of cell growth inhibition on CCRF-CEM, HL-60, HeLa S3, and L1210 cell lines showed significant activity in 8 new compounds. The most potent compounds were the above mentioned 6-dibromomethyl derivative (IC(50)=0.54, 1.7, 5.0, and 1.9 molL(-1)) and 7,N(2),N(4)-tribenzyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine (IC(50)=1.9, 2.7, 7.3, and 1.0 molL(-1)).
Otmar
Miroslav
M
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic. otmar@uochb.cas.cz
Masojídková
Milena
M
Votruba
Ivan
I
Holý
Antonín
A
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C495614:2,6-diamino-9-benzyl-9-deazapurine; D001372:Aza Compounds; D011687:Purines; C030985:purine