Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: a patent review (2008-2018).

INTRODUCTION: Human carbonic anhydrases (CA, EC 4.2.1.1) IX and XII are tumor-associated proteins, being part of the molecular machinery that tumor cells build as adaptive responses to hypoxia and acidic conditions characteristic of the 'glycolytic shift' of many tumors. A wealth of research depicts CA IX and CA XII as biomarkers and therapeutic targets for various cancer types. AREAS COVERED: The review presents an overview of the role of CA IX and CA XII in hypoxic tumors physio-pathology as well as the principal molecular, structural, and catalytic features of both isozymes. The review then covers the patent literature of medically relevant inhibitors of the tumor-associated CAs produced during the period 2008-2018. EXPERT OPINION: A variety of approaches and design strategies were reported which afford CA IX/XII-specific inhibitors and avoid the compromising effects of isoforms-promiscuous compounds. Access to the crystal structures of human CAs isoforms have improved structure-based drug design campaigns related to zinc-binder chemotypes. Nevertheless, great potential still resides in non-classical CAIs that exhibit alternative binding mechanisms able to further distinguish the various active sites architecture. CA IX inhibitors hybrids/conjugates are increasingly emerging in the field as promising therapeutic tools to combine CA inhibition to the anticancer effects of other moieties or antitumor drugs.