Relationship between carbonic anhydrase (CA) and cancer has been known for more than 20 years but only recently two isozymes (IX and XII) overexpressed in solid tumor have been identified, cloned and sequenced. Membrane-bound hCA isozymes IX and XII are expressed at high levels and with a high prevalence in different tumor tissues, whose normal counterparts do not contain these proteins. Thus, specifically targeting the tumor associated isoforms hCA IX and XII over the main off target isoforms hCA I and II, which have a physiological relevance, using specific inhibitors is a promising strategy in the cancer therapy.

[6]-Paradol, a pungent phenolic compound present in certain Zingiberaceae plants (ginger, etc.), is known to have cytotoxicity activity against human leukemia cells. Also other ingredients of ginger like [6]-shogaol showed to inhibit non-small cell lung cancer cells. All these compounds contain the 4-hydroxy-3-methoxyphenyl moiety also found in vanillin. Recently our group showed that attachment of carbohydrate tails to phenoxy moiety leads to highly selective CA IX inhibitors. The aim of the present work is to study new C-glycoside incorporating the 4-hydroxy-3-methoxyphenyl moiety as selective inhibitor of tumor associated CA isoforms. We present the hCA (I, II, IX and XII) inhibition profile of the carbohydrate derivatives and also other ones prepared by aldol reaction of alkyl and aryl ketones. Docking analysis is discussed showing that the high selectivity could be explained in terms of a binding pocket out of the CA active site. Thus, discovery of these selective IX and XII inhibitors will be a promising step in the strategy for an effective cancer therapy.