The selective inhibition of cancer-associated human carbonic anhydrase (CA) enzymes, specifically CA IX and XII, has been validated as a mechanistically novel approach toward personalized cancer management. Herein we report the design and synthesis of a panel of 24 novel glycoconjugate primary sulfonamides that bind to the extracellular catalytic domain of CA IX and XII. These compounds were synthesized from variably acylated glycopyranosyl azides and either 3- or 4-ethynyl benzene sulfonamide using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC). The CA enzyme inhibition profile for all compounds was determined, while in vitro metabolic stability, plasma stability, and plasma protein binding for a representative set of compounds was measured. Our findings demonstrate the influence of the differing acyl groups on these key biopharmaceutical properties, confirming that acyl group protected carbohydrate-based sulfonamides have potential as prodrugs for selectively targeting the extracellular cancer-associated CA enzymes.
A prodrug approach toward cancer-related carbonic anhydrase inhibition / Carroux, Cindy J.; Rankin, Gregory M.; Moeker, Janina; Bornaghi, Laurent F.; Katneni, Kasiram; Morizzi, Julia; Charman, Susan A.; Vullo, Daniela; Supuran, Claudiu T; Poulsen, Sally-Ann. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:(2013), pp. 9623-9634. [10.1021/jm401163e]
A prodrug approach toward cancer-related carbonic anhydrase inhibition
VULLO, DANIELA;SUPURAN, CLAUDIU TRANDAFIR;
2013
Abstract
The selective inhibition of cancer-associated human carbonic anhydrase (CA) enzymes, specifically CA IX and XII, has been validated as a mechanistically novel approach toward personalized cancer management. Herein we report the design and synthesis of a panel of 24 novel glycoconjugate primary sulfonamides that bind to the extracellular catalytic domain of CA IX and XII. These compounds were synthesized from variably acylated glycopyranosyl azides and either 3- or 4-ethynyl benzene sulfonamide using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC). The CA enzyme inhibition profile for all compounds was determined, while in vitro metabolic stability, plasma stability, and plasma protein binding for a representative set of compounds was measured. Our findings demonstrate the influence of the differing acyl groups on these key biopharmaceutical properties, confirming that acyl group protected carbohydrate-based sulfonamides have potential as prodrugs for selectively targeting the extracellular cancer-associated CA enzymes.I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.