Iodoetherification as a strategy towards sp3-rich scaffolds for drug discovery.

Functionalised tetrahydropyran and spirooxepane scaffolds were prepared utilising an iodoetherification strategy and elaborated to demonstrate their potential use in library synthesis. The iodoetherification products could be readily transformed to the corresponding azides that could be further functionalised via copper-catalysed azide-alkyne cycloaddition or reduction to the amine. The lead-likeness and three-dimensionality of the scaffolds were examined and compared to commercial libraries.

Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones.

Cyclization of substituted thiosemicarbazones with α-bromo-4-cyanoacetophenone allows rapid single-step sustainable syntheses of 4-cyanophenyl-2-hydrazinylthiazoles libraries (30 examples, 66-79%). All show anticancer efficacy against HCT-116 and MCF-7 carcinoma cell lines with the majority being more active than cisplatin positive controls. The compounds 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f) and 2-(2-((pentafluorophenyl)methylene)-hydrazinyl)-4-(4-cyanophenyl)thiazole (3a') show optimal GI50 values (1.0 ± 0.1 µM and 1.7 ± 0.3 µM) against MCF-7 breast cancer cells. Against colorectal carcinoma HCT-116 cells, (2-(2-(3-bromothiophen-2-yl)methylene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3b'), 2-(2-(2-hydroxy-3-methylbenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f), 2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3n) and 2-(2-(1-(4-fluorophenyl)ethylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3w) are the most active (GI50 values: 1.6 ± 0.2, 1.6 ± 0.1, 1.1 ± 0.5 and 1.5 ± 0.8 µM respectively). Control studies with MRC-5 cells indicate appreciable selectivity towards the cancer cells targeted. Significant (p < 0.005) growth inhibition and cytotoxicity effects for the thiazoles 3 were corroborated by cell count and clonogenic assays using the same cancer cell lines at 5 and 10 µM agent concentrations. Cell cycle, caspase activation and Western blot assays demonstrated that compounds 3b' and 3f induce cancer cell death via caspase-dependent apoptosis. The combination of straight forward synthesis and high activity makes the thiazoles 3 an interesting lead for further development.

Synthesis of Highly Substituted 1,2-Diazetidin-3-ones, Small-Ring Scaffolds for Drug Discovery.

1,2-Diazetidin-3-ones are readily accessible, small ring scaffolds that upon functionalization have the potential to produce diverse 3-dimensional structures for drug discovery. Thus, treatment of diazo hydrazides, obtained from simple hydrazides and malonyl half ester derivatives, followed by diazo transfer, with catalytic amounts of rhodium(II) acetate dimer results in intramolecular carbenoid N-H insertion to give 1,2-diazetidin-3-ones. Although subsequent functionalization reactions could be hampered by the lability of the 4-membered ring, a wide range of new derivatives was available by deprotection at N-1, and subsequent amide or urea formation. The structures of four four-membered rings was confirmed by X-ray crystallography; the compounds showed modest growth inhibitory activity in mammary carcinoma cells.

Densely functionalised spirocyclic oxetane-piperidine scaffolds for drug discovery.

A spirocyclic, sp3-atom rich oxetane-containing scaffold was synthesised in just two steps via a gold catalysed propargylic alcohol rearrangement. The key gold cyclisation can be undertaken on a 40 g scale allowing the preparation of 419 lead-like compounds based on the scaffold for the European Lead Factory.

C-H Insertion as a Key Step to Spiro-Oxetanes, Scaffolds for Drug Discovery.

A new route to spiro-oxetanes, potential scaffolds for drug discovery, is described. The route is based on the selective 1,4-C-H insertion reactions of metallocarbenes, generated from simple carbonyl precursors in flow or batch mode, to give spiro-ß-lactones that are rapidly converted into spiro-oxetanes. The three-dimensional and lead-like properties of spiro-oxetanes are illustrated by the conversion of the 1-oxa-7-azaspiro[3,5]nonane scaffold into a range of functionalized derivatives.

Synthesis of 4-aminotetrahydropyran scaffolds for drug discovery.

Functionalised tetrahydropyran scaffolds were prepared using a tethered enol-ether Prins cyclisation and elaborated to show their potential use in library synthesis. The key 4-hydroxytetrahydropyran scaffold could be readily manipulated to the 4-azidotetrahydropyran that could be elaborated via copper catalysed azide-alkyne cycloaddition or by reduction to the amine, to provide sp3-rich scaffolds useful for drug discovery.

Seven-membered ring scaffolds for drug discovery: Access to functionalised azepanes and oxepanes through diazocarbonyl chemistry.

Functionalised azepane and oxepane scaffolds were prepared using diazocarbonyl chemistry and elaborated to show their potential use in library synthesis. Key dicarbonyl containing seven-membered rings were functionalised via diastereoselective Luche reduction of the ketone followed by manipulation of the ester and amine groups. Further scaffolds could be accessed by C-alkylation of the dicarbonyl compounds. In addition, an oxepane containing amino acid could be prepared via a diastereoselective enamine reduction.

Synthesis and biological evaluation of nitric oxide-donating analogues of sulindac for prostate cancer treatment.

A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac-NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC50 values of 6.1±4.1 and 12.1±3.2µM, respectively, coupled with observed nitric oxide release.

Novel amino acids: synthesis of furoxan and sydnonimine containing amino acids and peptides as potential nitric oxide releasing motifs.

The incorporation of furoxan and sydnonimine ring systems into amino acid side chains is demonstrated with the preparation of four novel amino acids which carry these nitric oxide-releasing motifs. N-((4-Nitrophenoxy)carbonyl)-3-phenylsydnonimine 9 and bis(phenylsulfonyl)furoxan 10 are the key intermediates for introducing the heterocycle side chains onto appropriate amine and alcohol functionalities respectively. Furoxan 5 and 7 both displayed NO release based on determination of nitrite production. Orthogonal amino acid protecting group strategies were deployed to demonstrate that the amino acids could be incorporated into peptide frameworks. By way of demonstration the amino acids were placed centrally into several tripeptide motifs. Griess test assays showed that these amino acids released NO in the presence of γ-glutathione (GST).