Trimethylsilylacetonitrile (TMSAN)

(A) The condensation of TMSAN with ketones in the presence of the catalytic t-Bu-P4 base to give cyanoalkenes has been reported;3 title compounds were prepared in a 63-80% yield. The reaction was also extended to the condensation of TMSAN with N-arylformanilides (ArNRCHO) in the preparation of enamine derivatives. (Chemical Equation Presented). (B) The addition of TMSAN to the carbonyl group of benzaldehyde catalyzed by KF/Al2O3 in THF allows the preparation of 3-phenyl-3-(trimethylsilyloxy)propionitrile as the major product (85%), together with cinnamonitrile (15%). A change of the solvent to DMF leads to the α,β-unsaturated nitrile as main product (61%).4 (Chemical Equation Presented). (C) Langer and co-workers reported a one-pot cyclization of epibromohydrin (EBH) with TMSAN in the presence of a strong base and catalyzed by a Lewis acid to form trimethylsilylcyano cyclopropane with excellent diasteroselectivity (E/Z > 98:2) and moderate yield (65%). 5 (Chemical Equation Presented). (D) Recently, 2-(2-cyanoethyl) aziridines were obtained by treatment of TMSAN with an equimolecular amount of n-BuLi followed by the addition of 1-arylmethyl-2-(bromomethyl)-aziridines. 6 Title compounds were obtained in moderate yield (41-65%). (Chemical Equation Presented). (E) TMSAN has been used as a nucleophile to open the acetal ring in sugar spiroketals. The nucleophilic attack of TMSAN on the anomeric carbon can take place either through the nitrogen atom or through the methylenic carbon7 to give a spironucleoside or a spiro-C-glycoside, respectively. (Chemical Equation Presented). (F) There are a few reports of cyanomethylation of aldehydes and ketones using TMSAN as nucleophile. Suto et al. have developed a copper fluoride catalyzed addition to the carbonyl group with high yields.8 (Chemical Equation Presented). (G) β-Amino nitriles can be obtained by the condensation between chiral N-(tert- butylsulfonyl)imines and TMSAN in the presence of a Lewis base with excellent diasteroselectivity.9 Optimization of the reaction conditions by changing the Lewis base, temperature, and solvent showed that the best yields and diasteroisomeric ratios were obtained when PhONn-Bu4 was used as a Lewis base in THF at -78°C. (Chemical Equation Presented). (H) Wu and Hartwig described the monoarylation of nitriles by means of the coupling of TMSAN with aryl halides in the presence of palladium catalysts and zinc fluoride. 10 (Chemical Equation Presented). (I) A singular reaction of transannulation of pyridotriazoles with TMSAN in the presence of Rh 2(OAc)4 to afford a N-fused imidazopyridine was described by Chuprakov et al.11 Rhodium-catalyzed transannulations of 1-sulfonyl triazoles were recently reported by the same group.12 (Chemical Equation Presented). (J) Nakao et al. reported the Ni-catalyzed carbocyanation of 4-octyne with TMSAN in the presence of a Lewis acid (LA) to give a highly substituted allylsilane in modest yield (29%).13 (Chemical Equation Presented)

2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (Ki within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (Ki > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.España MICINN (PID2020-116460RB-I00, PGC2018- 094503-B-C22)Junta de Andalucía (FQM134)Gobierno de Canarias ProID202001010

Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach.Dirección General de Investigación de España. CTQ2016-78703-PJunta de Andalucía. FQM134Fondo Europeo de Desarrollo Regional (FEDER) y Consejo Nacional de Ciencia y Tecnología de México (CONACYT). CB-2015/257465Ministerio de Ciencia, Innovación y Universidades y Agencia Estatal de Investigación de España y Fondos FEDER de la Unión Europea (MCIU/AEI/FEDER). PGC2018-094503-B-C2

Thio- and selenosemicarbazones as antiprotozoal agents against Trypanosoma cruzi and Trichomonas vaginalis

Herein, we report the preparation of a panel of Schiff bases analogues as antiprotozoal agents by modification of the stereoelectronic effects of the substituents on N-1 and N-4 and the nature of the chalcogen atom (S, Se). These compounds were evaluated towards Trypanosoma cruzi and Trichomonas vaginalis. Thiosemicarbazide 31 showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC50 (31)=28.72 μM (CL-B5 strain) and 33.65 μM (Y strain), IC50 (BZ)=25.31 μM (CL-B5) and 22.73 μM (Y); it lacked toxicity over mammalian cells (CC50 > 256 µM). Thiosemicarbazones 49, 51 and 63 showed remarkable trichomonacidal effects (IC50 =16.39, 14.84 and 14.89 µM) and no unspecific cytotoxicity towards Vero cells (CC50 ≥ 275 µM). Selenoisosters 74 and 75 presented a slightly enhanced activity (IC50=11.10 and 11.02 µM, respectively). Hydrogenosome membrane potential and structural changes were analysed to get more insight into the trichomonacidal mechanism.Junta de Andalucía Grant PID2020- 116460RB-I00, funded by MCIN/AEI/10.13039/50110001103

Syntheses and medicinal chemistry of spiro heterocyclic steroids

There is compelling evidence that incorporating a heterocyclic moiety into a steroid can alter its pharmacological and pharmacokinetic properties, driving intense interest in the synthesis of such hybrids among research groups. In this review, we present an overview of recent synthetic methodologies, spanning the period from 2000 to 2023, for the preparation of spiro heterocyclic steroids. The compounds surveyed encompass four-, five-, six-, and seven-membered heterocycles appended to various positions of steroidal backbones, with spirocycles containing oxygen, nitrogen, and sulfur atoms being predominant. The outlined synthetic procedures emphasize the pivotal steps for constructing the heterocycles, often accompanied by a detailed account of the overall synthesis pathway. The review encompasses innovative compounds, including bis-steroids linked by a spiro heterocycle and steroids conjugated to heterocyclic moieties containing three or more (hetero)cycles. Moreover, many compounds are accompanied by data on their biological activities, such as antiproliferative, antimalarial, antimicrobial, antifungal, steroid antagonist, and enzyme inhibition, among others, aimed at furnishing pertinent insights for the future design of more potent and selective drugs

Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs

Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields. Title compounds were tested in vitro against a panel of six human tumor cell lines, named A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon), and the results were compared with steroidal chemotherapeutic agents (abiraterone and galeterone); the A-ring of the steroidal backbone, the nature of the heterocycle and the N-substituents proved to be essential motifs for establishing structure-activity relationships concerning not only the potency but also the selectivity against tumor cell lines. Estrone derivatives, particularly those bearing a spiranic 2-aminooxazoline scaffold were found to be the most active compounds, with GI50 values ranging from the low micromolar to the submicromolar level (0.34–1.5 μM). Noteworthy, the lead compounds showed a remarkable increase in activity against the resistant cancer cell lines (T-47D and WiDr) compared to the anticancer reference drugs (up to 120-fold).CONACYT-México 24032

Synthesis and Evaluation of Pyrimidine Steroids as Antiproliferative Agents

A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,β-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI50 values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range

Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors

The involvement of carbonic anhydrases (CAs) in a myriad of biological events makes the development of new inhibitors of these metalloenzymes a hot topic in current Medicinal Chemistry. In particular, CA IX and XII are membrane-bound enzymes, responsible for tumour survival and chemoresistance. Herein, a bicyclic carbohydrate-based hydrophilic tail (imidazolidine-2-thione) has been appended to a CA-targeting pharmacophore (arylsulfonamide, coumarin) with the aim of studying the influence of the conformational restriction of the tail on the CA inhibition. For this purpose, the coupling of sulfonamido- or coumarin-based isothiocyanates with reducing 2-aminosugars, followed by the sequential acid-promoted intramolecular cyclization of the corresponding thiourea and dehydration reactions, afforded the corresponding bicyclic imidazoline-2-thiones in good overall yield. The effects of the carbohydrate configuration, the position of the sulfonamido motif on the aryl fragment, and the tether length and substitution pattern on the coumarin were analysed in the in vitro inhibition of human CAs. Regarding sulfonamido-based inhibitors, the best template turned out to be a d-galacto-configured carbohydrate residue, meta-substitution on the aryl moiety (9b), with Ki against CA XII within the low nM range (5.1 nM), and remarkable selectivity indexes (1531 for CA I and 181.9 for CA II); this provided an enhanced profile in terms of potency and selectivity compared to more flexible linear thioureas 1–4 and the drug acetazolamide (AAZ), used herein as a reference compound. For coumarins, the strongest activities were found for substituents devoid of steric hindrance (Me, Cl), and short linkages; derivatives 24h and 24a were found to be the most potent inhibitors against CA IX and XII, respectively (Ki = 6.8, 10.1 nM), and also endowed with outstanding selectivity (Ki > 100 µM against CA I, II, as off-target enzymes). Docking simulations were conducted on 9b and 24h to gain more insight into the key inhibitor–enzyme interactions.Ministerio de Ciencia e Innovación PID2020-116460RB-I00, PID2021-123059OB-I00Junta de Andalucía FQM134Italian Ministry for University and Research (MIUR) 2017XYBP2

Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer's disease

Concerned by the urgent need to explore new approaches for the treatment of Alzheimer's disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain. Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine. The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD; it turned out to be a strong inhibitor of BuChE (IC50 = 0.46 µM), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC50 = 2.2 µM). This compound exhibited a roughly 12-fold increase in activity compared to galantamine, one of the currently marketed drugs against AD, and a selective AChE inhibitor, and virtually the same activity as rivastigmine, a selective BuChE inhibitor. Furthermore, it was also endowed with a strong inhibitory activity against human OGA, within the nanomolar range (IC50 = 0.053 µM for hOGA, >100 µM for hHexB), and, thus, with an outstanding selectivity (IC50(hHexB)/IC50(hOGA) > 1887). The title compounds also exhibited an excellent selectivity against a panel of glycosidases and a negligible cytotoxicity against tumor and non-tumor cell lines. Docking simulations performed on the three target enzymes (AChE, BuChE, and OGA) revealed the key interactions to rationalize the biological data.Ministerio de Ciencia e Innovación PID2020-116460RB-I00Junta de Andalucía FQM-134, FQM- 345Comunidad Autónoma de Canarias ProID2020010101Mexican CONACYT CB-2015/2574