Induction of growth inhibition and G1 arrest in human cancer cell lines by relatively low-toxic diamantane derivatives

We describe the discovery of a novel series of antitumor diamantane derivatives which induces G(1) arrest in Colo 205 cells. Eight diamantane derivatives were screened for their activity in vitro against 60 human cancer cell lines in the National Cancer Institute (NCI)'s anticancer drug screen. The relationships between structure and in vitro antitumor activity are discussed. The structure-activity relationship (SAR) study of diamantane derivatives clarified that the conformation of 1,6-bis(4-(4-aminophenoxy)phenyl)diamantane (1,6-DPDONH2) was essential for significant antitumor activity. Very strong growth inhibition of 1,6-DPDONH2 (NSC-706829) was observed against one colon cancer line (Colo 205), four melanoma lines (MALME-3M, M14, SK-MEL-5 and UACC-257) and two breast cancer lines (MDA-MB-435 and MDA-N) with GI(50) < 1.0 muM, i.e. below 0.01, 0.23, 0.48, 0.5, 0.32, 0.26 and 0.28 muM, respectively. 1,6-DPDONH2 also exhibited particular selectivity against one colon cancer line (Colo 205), four melanoma lines (MALME-3M, M14, SK-MEL-5 and UACC-257) and two breast cancer lines (MAD-MB-435 and MDA-N) with GI(50) less than or equal to 0.5 muM. In the same cancer subpanel, the selectivity of 1,6-DPDONH2 between these seven most sensitive lines and the least sensitive line ranged from 40- to 100-fold. With the exception of melanoma lines, 1,6-bis(4-(4-amino-3-hydroxyphenoxy)phenyl)diamantane (1,6-DPD/OH/NH2) (NSC-706831) possessed stronger activity than 1,6-DPDONH2 against almost all tested cancer lines. Very strong growth inhibition of 1,6-DPD/OH/NH2 was observed against one leukemia line (HL-60(TB)), one NSCLC line (HOP-92), one ovarian cancer line (OVCAR-8) and one breast cancer line (T-47D) with GI(50) < 1.0 muM, i.e. 0.50, 0.85, 0.62 and 0.75 muM, respectively. (C) 2004 Lippincott Williams Wilkins.