Search

A series of new hybrid compounds was prepared combining tetrahydropyran rings with different aromatic systems by means of a 1,2,3-triazole, using a building block strategy. The design of these structures was guided by Lead-Likeness and Molecular Analysis (LLAMA) software, adding modifications to our most potent scaffold (the tetrahydropyran ring) to generate promising "lead-like" candidates, which were subsequently compared against reported anticancer compounds. Our synthesized compounds demonstrated significant antiproliferative activity when compared with the standards cisplatin and 5-fluorouracil, across a panel of six different tumor cell lines. Moreover, compared with our group's previous hybrid compounds, these new structures exhibit similar activity while offering simpler synthesis and greater potential for structural diversification, a fact that was previously an issue. Further investigations on the most active compounds included assessments of reproductive cell survival, inhibition of cell migration, and effects on nuclear morphology, indicating potential diverse mechanisms of action for these compounds. Pharmacokinetic properties were also calculated for the whole series of compounds using the pkCSM online software., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4'-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N 3 -OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91-98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A series of triazole linked tetrahydropyran–oxazole hybrids was synthesized based on a previously reported lead compound with selective antiproliferative activity against human tumour cell lines. The series was prepared to evaluate the impact of LogP and different modifications in the activity, and the new compounds were assayed against A549, HBL‐100, HeLa, SW1573, T‐47D, and WiDr cell lines. Also, the potentiality to be P‐gp substrate was tested. The compounds exhibited good antiproliferative results when compared with the standards cisplatin and 5‐fluorouracil. In silico studies to evaluate pharmacokinetic properties using pkCSM software were also carried out. [ABSTRACT FROM AUTHOR]

The role of carbonic anhydrases isoforms (CAs) IX and XII in the pathogenesis and progression of many types of solid tumors is well known. In this context, selective CA inhibitors (CAIs) towards the mentioned isoforms is a validated strategy for the development of agents to target cancer. For this purpose, novel coumarin derivatives based on the hybridization with arylsulfonamide or biotin scaffolds were synthesized and tested as inhibitors of four different human carbonic anhydrases isoforms: hCA I, II, IX and XII. Coumarin-sulfonamide derived 27 , with a thiourea moiety and triazole as linker, showed the highest inhibition activity against hCA XII with an inhibition constant (K I) of 7.5 nM and afforded a very good selectivity over hCA I. Compound 32 was the most potent inhibitor against hCA IX (K I = 6.3 nM), 4-fold stronger than the drug acetazolamide AAZ (K I = 25 nM), used herein as a reference compound, and showed remarkable selectivity over hCA I and II. The coumarin-biotin derivatives 37 – 39 showed outstanding selectivity towards on-target enzymes (hCA IX and XII) and appear as plausible leads for designing of CAIs. [Display omitted] • Synthesis of coumarin derivatives based on the hybridization with arylsulfonamide or biotin scaffolds. • Biological evaluation: Carbonic Anhydrase inhibitory activity. • Low nanomolar activities were achieved. • Coumarins derivatives bearing biotin as scaffold sharply increased the selectivity towards hCA IX and XII. • Molecular Docking studies were used to predict the binding properties of the most relevant inhibitors with CAs. [ABSTRACT FROM AUTHOR]