Cancer targeting using carbonic anhydrase isoform ix inhibitors

Abstract

The present invention concerns novel carbonic anhydrase IX inhibitors comprising a nitroimidazole moiety and their use in therapy of hypoxic conditions, in particular cancer treatment, especially chemotherapy and radiotherapy. The compounds of the invention have an increased specificity for the carbonic anhydrase IX enzyme compared to the art. The present invention relates to novel nitroimidazole derivates represented by formula (1), wherein R1, R2, and Z are as defined herein:

Description

FIELD OF THE INVENTION[0001]The present invention concerns novel carbonic anhydrase IX inhibitors comprising a nitroimidazole moiety including their use in cancer treatment, especially radiotherapy.BACKGROUND[0002]Cancer is a leading cause of death and accounts for approximately 13% of all deaths in the world. Most cancers form solid tumors in tissues like head and neck, colon, breast, lung, liver and stomach, and are often characterized by low oxygen concentrations (hypoxia) and acidification of the microenvironment surrounding the tumor cells. Hypoxia and acidification of the extratumoral environment are both associated with aggressive tumor growth, metastasis formation and poor response to radiotherapy, surgery and / or to anticancer chemotherapy. The most important pathway that acts on changes in oxygen concentration is the ‘Hypoxia Inducible Factor-1 pathway’ (HIF-1 pathway). Under hypoxic conditions, the transcription factor HIF-1α is stabilized and binds to HIF-1β. The formed c...

AI Technical Summary

Benefits of technology

The patent text describes a new group of compounds that have an increased ability to target and kill cancer cells. These compounds are also more effective at treating tumors with radiation, which is commonly used in cancer treatment. The compounds have a unique structure and work by inhibiting a specific enzyme that is overactive in cancer cells. The text also mentions that the compounds can reduce the production of lactic acid, which is associated with a more acidic tumor environment. Overall, the compounds described in this patent have the potential to improve the effectiveness of cancer treatment.

Problems solved by technology

Hypoxia and acidification of the extratumoral environment are both associated with aggressive tumor growth, metastasis formation and poor response to radiotherapy, surgery and / or to anticancer chemotherapy.

Furthermore, CA IX associated with worse relapse-free survival and overall survival in patients with invasive tumors.

Furthermore, because most of the small-molecules inhibitors of HIF-1 affect multiple signalling pathways and / or targets indirectly associated with HIF, assessment of their activity as HIF inhibitors cannot be based on therapeutic efficacy, which might be unrelated to HIF inhibition (Melillo, 2006).

However, the critical problem in designing these inhibitors is the high number of isozymes, the diffuse localization in tissues and the lack of isozyme selectivity of the presently available inhibitors.

However when no or little oxygen is present, what is the case in hypoxic tumors, less reactive oxygen species are formed and the irradiation is not as effective.

The most likely explanation is the fact that the misonidazole doses were too low, limited by the risk of neurotoxicity.

Alternative, better radiosensitizing drugs, such as etanidazole and pimonidazole, were synthesized and tested, but clinical results did not result in a significant therapeutic benefit.

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