The present disclosure is generally directed to inhibitors of Hypoxia Inducible Factor (HIF-1), more particularly to 2,2-dimethylbenzopyran compounds, derivatives thereof, and methods of their use including but not limited to anti-tumor therapies and disorders leading to ischemia (stroke, ischemic heart disease, etc.). 2. Related Art
According to the American Cancer Society, approximately 1.3 million Americans are estimated to be diagnosed with invasive cancer in 2003. The National Cancer Institutes estimates that approximately 8.9 million Americans had a history of cancer in 2003, and approximate 1,500 cancer-related deaths per day are expected in 2003. Because of the staggering number of cancer-related deaths and new cases, new medicines and methods of treatment are needed. Although recent advances have increased our understanding of some of the mechanisms leading to cancer, effective treatments for cancer remain in high demand.
Cancer can be a fatal disease, in part, because cancer can spread or metastasize throughout an organism. Metastasis plays a major role in the morbidity and mortality of breast cancer (Ford, K. et al. Breast cancer screening, diagnosis, and treatment. Dis. Mon., 45: 333-405 (1999)). Breast cancer metastasizes in a stereotypical pattern resulting in lesions found in the lymph node, lung, liver, and bone marrow. Generally, cancer cells lose differentiated properties, proper tissue compartmetalization, cell-cell attachment as well as obtain altered cell substratum attachment, altered cytoskeletal organization, cell locomotion, and the ability to survive at distant sites.
Treatments for invasive cancers such as breast cancer historically include surgery, radiation, anti-hormonal therapy, and chemotherapy. Although each therapy has some degree of success, the failure to achieve a cure in approximately 70% of patients is due to a primary lack of therapeutic effect on undetected or detected metastases and to acquired drug and hormonal resistance during therapy (Fidler, I. and Nicolson, G. L. Concepts and mechanisms of breast cancer metastases. In Bland, K. I., Copeland, E. M. (eds): The Breast. Philadelphia: WB Saunders, 1991, p 395).
Hypoxia is a major hindrance to effective solid tumor therapy. The microenvironment of rapid growing solid tumors is associated with increased energy demand and diminished vascular supply, resulting in focal areas of prominent hypoxia, regions with reduced oxygen tensions (Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82, 4-6(1989)). Tissue oxygen electrode measurements taken in cancer patients showed a median range of oxygen partial pressure of 10 to 30 mmHg, with a significant proportion of readings below 2.5 mmHg, whereas those in normal tissues ranged from 24 to 66 mg (Vaupel P. W. Oxygenation of solid tumors. In Drug Resistance in Oncology. Teicher, B. A. (ed.) 53-85 (Marcel Dekker, New York, 1993). In the absence of oxygen, which is the most electron-affinic molecule in cells and reacts chemically with the fundamental biological lesion produced by ionizing radiation, radiotherapy is severely compromised in its ability to kill hypoxic tumor cells (Gray L. H. et al. Concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26, 638-648 (1953). On the other hand, hypoxia (and possibly hypoxia-associated deficiencies in other nutrients such as glucose) causes tumor cells to stop or slow their rate of progression through the cell cycle (Amellem O, Pettersen E O. Cell inactivation and cell cycle inhibition as induced by extreme hypoxia: the possible role of cell cycle arrest as a protection against hypoxia-induced lethal damage. Cell Prolif 24, 127-141 (1991)). Because most anticancer drugs are more effective against rapidly proliferating cells than slowly or non-proliferating cells, this slowing of cell proliferation leads to decreased cell killing. Chemotherapy is further affected by hypoxia as chemotherapeutic drugs are delivered systemically and the diffusion of these into the tumor makes the hypoxic regions exposed to less drug than the oxygenated cells proximal to the vessels. Moreover, the multidrug resistance (MDR1) gene product P-glycoprotein is induced by ambient hypoxia (Comerford K. M. et al. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62, 3387-94(2002)). Hypoxia also drives genetic changes in tumors such as loss of p53 tumor suppressor gene (Brown, J. M., and Giaccia, A. J. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 58(7):1408-16 (1998)).
Finally, hypoxic regions are expected to be less amenable to immunotherapy due to distance from nearby vessels and compromised lymphocyte function in a hypoxic environment. Tumor cells in this aberrant environment are therefore often resistant to radio- and chemotherapy (reviewed in Brown, J. M., and Giaccia, A. J. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 58(7):1408-16 (1998).
Accordingly, there is a need for new and effective treatments for cancer. In particular, there is a need for new and effective treatments that address hypoxia and its role in hyperproliferative pathologies.