The present invention relates to compounds with some structural similarities to bufadienolide compounds disclosed in the prior art. For a review of bufadienolides see Huimin Gao et al in Nat. Prod. Rep., 2011, 28, 953.
The bufadienolide compounds reported in the prior art are natural steroids, originally isolated from terrestrial natural sources such as plants of the families Crassulaceae, Hyacinthaceae, Iridaceae, Melianthaceae, Ranunculaceae, and Santalaceaethe, and animals of the genus Bufo (toads), Photinus (fireflies), and Rhabdophis (snakes) (Steyn et al. Nat. Prod. Rep. 1998, 15, 397-413; Krenn et al. Phytochemistry, 1998, 48(1), 1-29).
Among these bufadienolide compounds, Scilliroside and other Scilla compounds have been isolated from the red squill, Urginea maritima, and are disclosed to be highly toxic, specially Scilliroside which affects the cardiovascular and central nervous systems, causing convulsions and death (Verbiscar et al. J. Agric. Food Chem. 1986, 34, 973-979; Kopp et al. Phytochemistry, 1996, 42(2), 513-522). Majinda et al. also isolated bufadienolide compounds from Urginea sanguinea, which make the plant unsafe to be used as a medicinal plant (Planta Med. 1997, 63, 188-190).
The antiviral activity against a series of rhinoviruses and the anti-herpetic activity of several bufadienolide compounds were evaluated by Kamano et al. (Chem. Pharm. Bull. 1988, 36(1), 326-332) and Takechi et al. (Phytochemistry, 1996, 41(1), 125-127), respectively, and they found that most of the compounds displayed some inhibitory activity.
Additionally, the cytotoxic activity of several bufadienolide compounds has been evaluated by several authors. Specifically, Jing et al. reported that bufalin has a potent growth-inhibitory effect on human cancer cells of leukaemia (HL-60, ML1, U937, and K562 cell lines), epithelioid carcinoma (HeLa cell line), hepatoma (PLC/PRF/5 cell line), and epidermoid carcinoma (A431 cell line), but it is less potent on mouse leukaemia M1, melanoma B16, and lymphoid neoplasm P388 cell lines and rat hepatoma AH66 and chromaffin cell PC12 cell lines. They also found that bufalin induces typical apoptosis in human leukaemia HL-60 cell line but not in human leukocytes (Jpn. J. Cancer Res. 1994, 85(6), 645-651).
Kupchan et al. disclosed several bufadienolide compounds isolated from Bersama abyssinica which showed inhibitory activity against human carcinoma of the nasopharynx (KB) cell line (Bioorg. Chem. 1971, 1, 13-31; J. Org. Chem. 1971, 36(18), 2611-2616).
Kamano et al. evaluated the cytotoxic activity of 80 bufadienolide and cardenolide compounds, isolated from the Chinese drug Ch'an Su (obtained from the skin glands of toads such as Bufo gargarizans), against a primary liver carcinoma PLC/PRF/5 cell line and the colchicine-resistant cell line of PLC/PRF/5. Of them, 16 were shown to have potent cytotoxicities (IC50<10−3 μg/mL) against PLC/PRF/5 cell line (Bioorg. Med. Chem. 1998, 6, 1103-1115; J. Med. Chem. 2002, 45, 5440-5447). Additional bufadienolide compounds were isolated by Nogawa et al. from the same source, which were tested against human carcinoma of the nasopharyx (KB), human leukaemia (HL-60), murine leukaemia (MH60), pancreas adenocarcinoma (BXPC3), breast adenocarcinoma (MCF7), CNS glioblastoma (SF268), lung NSC (NCIH460), colon carcinoma (KM20L2), and prostate cancer (DU145) cell lines (J. Nat. Prod. 2001, 64, 1148-1152).
Ye et al. prepared novel bufadienolide compounds from bufalin by microbial hydroxylation. The compounds were tested against human hepatoma Bel-7402, human gastric cancer BGC-823, human cervical carcinoma HeLa, and human leukaemia HL-60 cell lines, showing some of them potent cytotoxicities comparable to that of bufalin (J. Steroid. Biochem. Mol. Biol. 2004, 91, 87-98; J. Nat. Prod. 2005, 68, 626-628).
Since cancer is a leading cause of death in animals and humans, several efforts have been and are still being undertaken in order to obtain an anticancer therapy active and safe to be administered to patients suffering from a cancer. The problem to be solved by the present invention is to provide compounds that are useful in the treatment of cancer.