A series of derivatives of a triazole analogue of thiamine has been synthesised. When tested as inhibitors of porcine pyruvate dehydrogenase, the benzoyl ester derivatives proved to be potent thiamine...
Thiamine is metabolized into the coenzyme thiamine diphosphate (ThDP). Interrupting thiamine utilization leads to disease states. Oxythiamine, a thiamine analogue, is metabolized into oxythiamine diphosphate (OxThDP), which inhibits ThDP-dependent enzymes. Oxythiamine has been used to validate thiamine utilization as an anti-malarial drug target. However, high oxythiamine doses are needed in vivo because of its rapid clearance, and its potency decreases dramatically with thiamine levels. We report herein cell-permeable thiamine analogues possessing a triazole ring and a hydroxamate tail replacing the thiazolium ring and diphosphate groups of ThDP. We characterize their broad-spectrum competitive inhibition of ThDP-dependent enzymes and of Plasmodium falciparum proliferation. We demonstrate how the cellular thiamine-utilization pathway can be probed by using our compounds and oxythiamine in parallel.
Cyanobacteria are reported as rich sources of secondary metabolites that provide biological activities such as enzyme inhibition and cytotoxicity. Ten depsipeptide derivatives (lyngbyabellins) were isolated from a Malaysian Moorea bouillonii and a Red Sea Okeania sp.: lyngbyabellins G (1), O (2), P (3), H (4), A (7), 27-deoxylyngbyabellin A (5), and homohydroxydolabellin (6). This study indicated that lyngbyabellins displayed cytotoxicity, antimalarial, and antifouling activities. The isolated compounds were tested for cytotoxic effect against human breast cancer cells (MCF7), for antifouling activity against Amphibalanus amphitrite barnacle larvae, and for antiplasmodial effect towards Plasmodium falciparum. Lyngbyabellins A and G displayed potent antiplasmodial effect against Plasmodium, whereas homohydroxydolabellin showed moderate effect. For antifouling activity, the side chain decreases the activity slightly, but the essential feature is the acyclic structure. As previously reported, the acyclic lyngbyabellins are less cytotoxic than the corresponding cyclic ones, and the side chain increases cytotoxicity. This study revealed that lyngbyabellins, despite being cytotoxic agents as previously reported, also exhibit antimalarial and antifouling activities. The unique chemical structures and functionalities of lyngbyabellin play an essential role in their biological activities.
Correction for ‘Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity’ by Alex H. Y. Chan et al., RSC Med. Chem., 2022, 13, 817–821, https://doi.org/10.1039/D2MD00085G.
Thiamine (vitamin B1) is metabolised into the coenzyme thiamine diphosphate (ThDP). Interrupting thiamine-utilisation leads to disease states and thiamine/ThDP analogues are commonly used as antagonists of thiamine-utilisation pathways to investigate the underlying pathophysiology. Oxythiamine, a thiamine analogue, uses the thiamine-utilising pathways for conversion into oxythiamine diphosphate (OxThDP), which binds to ThDP-dependent enzymes but lacks the catalytic activity of ThDP. Oxythiamine has been used to validate thiamine utilisation as an antimalarial drug target. However, high oxythiamine doses are often needed in vivo because 1) of its rapid clearance and 2) its potency decreases dramatically with thiamine levels. We report herein thiamine analogues possessing a triazole ring and a hydroxamate tail in place of the thiazolium ring and diphosphate group, respectively, of ThDP. We characterise their broad-spectrum inhibition of ThDP-dependent enzymes in biochemical and computational studies, and establish their ThDP-competitive action using Plasmodium falciparum as a model. We demonstrate how the cellular thiamine-utilisation pathway can be probed in mechanistic studies using our compounds and oxythiamine in parallel.
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