New bis-N9-(methylphenylmethyl)purine derivatives: Synthesis and antitumor activity

A series of ortho-, meta- and para-bis-N9-(methylphenylmethyl)purine derivatives 4–15 were obtained by two-step synthesis from various substituted chloropurines with α,α′-dichloroxylenes. These bis-N9-(methylphenylmethyl)purines 4–15 were evaluated for the primary cytotoxic activity against a panel of NCI-H460 (lung), MCF-7 (breast) and SF-268 (CNS) cancer cell lines. The ‘active’ compounds which reduced growth of cancer cells to ca. 32% or less, have been evaluated in a full panel of 60 human cancer cell lines over a 5-log dose range at the National Cancer Institute, Bethesda, MD. In this series, the most activity is correlated to the compounds derived from the 2,6-dichloropurines such as bis-9-[o-(methylphenylmethyl)]2,6-dichloropurine (5), bis-9-[m-(methylphenylmethyl)]2,6-dichloropurine (8), and bis-9-[p-(methylphenylmethyl)]2,6-dichloropurine (11). In particular compound 8 exhibited high sensitivity in leukemia cell lines and compounds 5, 8 and 11 exhibited consistent high sensitivity in many breast cancer cell lines. Compound 11 was the most potent in this series and exhibited GI50 < 0.01 μM sensitivity against non-small lung cancer EKVX, colon cancer HT-29, melanoma SK-MEL-28, renal cancer RXF 393, prostate cancer DU-145 and several breast cancer HS 578T and BT-549 cell lines.

In this paper, a series of ortho-, meta- and para-bis-N9-(methylphenylmethyl)purine derivatives were obtained by a two step synthesis and evaluated for their in vitro antitumor activity. Compounds derived from 2,6-dichloropurine showed the most promising activity.Figure optionsDownload as PowerPoint slide