Natural Product Polyamines That Inhibit Human Carbonic Anhydrases

Abstract

Natural product compound collections have proven an effective way to access chemical diversity and recent findings have identified phenolic, coumarin, and polyamine natural products as atypical chemotypes that inhibit carbonic anhydrases (CAs). CA enzymes are implicated as targets of variable drug therapeutic classes and the discovery of selective, drug-like CA inhibitors is essential. Just two natural product polyamines, spermine and spermidine, have until now been investigated as CA inhibitors. In this study, five more complex natural product polyamines 1–5, derived from either marine sponge or fungi, were considered for inhibition of six different human CA isozymes of interest in therapeutic drug development. All compounds share a simple polyamine core fragment, either spermine or spermidine, yet display substantially different structure activity relationships for CA inhibition. Notably, polyamines 1–5 were submicromolar inhibitors of the cancer drug target CA IX, this is more potent than either spermine or spermidine.

Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic bacterium Pseudoalteromonas haloplanktis

“…26,[39][40][41][42][43][44][45][46][47][48][49][50] Their biochemical features are known in detail for at least four classes, together with their distribution and role in various organisms. 32,33,41,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] Inhibition and activation studies of many such enzymes from vertebrates, protozoa, fungi and bacteria have shown that they are drug targets for obtaining pharmacological agents of the diuretic, antiglaucoma, antiobesity, antiepileptic, anticancer or anti-infective type. [55][56][57][58]60 Many such enzymes also possess biotechnologic applications for biomimetic CO 2 capture processes.…”

Polyamines and α-Carbonic Anhydrases

“…Herein we report on polyamines of natural origin, such as putrescine 1, spermidine 2 and spermine 3 ( Figure 1) as well as their structurally related derivatives of synthetic origin [10] or natural sources [11] which have, until now, been investigated as human (h) Carbonic Anhydrase (CA) inhibitors. Putrescine 1, spermidine 2 and spermine 3 represent the main pool of polyamines in the eukaryotic cells and are all derived from decarboxylation reactions of ornithine or S-adenosyl-methionine amino acids by the enzyme ornithine decarboxylase (ODC) [8].…”

“…Another contribution in the field was from us in collaboration with the Davis Group at Eskitis on the series of spermidine secondary metabolites 27-31 ( Figure 6) [11]. Direct Structure-Activity-Relationship SAR between the CA inhibition and the chain length is also evident when comparing the kinetic data of the N-polysubstituted spermine derivatives 23-25 with the corresponding shorter analogues 19-22.…”

“…Another contribution in the field was from us in collaboration with the Davis Group at Eskitis on the series of spermidine secondary metabolites 27-31 ( Figure 6) [11]. Anthelliformisamines A-C 27-29 were isolated from the marine sponge Suberea ianthelliformis [24], spermatinamine 30 from the sponge Pseudoceratina sp.…”

“…They were all previously considered for their antibacterial [24], antimalarial [28] and anticancer properties [29]. Table 2 reports the kinetic data of compounds 27-31 against the physiologically relevant hCAs I, II, IV, IX and XII [11]. Table 2.…”