Potent Dual BET/HDAC Inhibitors for Efficient Treatment of Pancreatic Cancer

As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small‐molecule inhibitors that simultaneously target bromodomain and extra‐terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor ( 13 a ) is identified to possess excellent and balanced activities against BRD4 BD1 (IC₅₀=11 nm ) and HDAC1 (IC₅₀=21 nm ). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)‐JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer.     

Selective Killing of Breast Cancer Cells by Doxorubicin‐Loaded Fluorescent Gold Nanoclusters: Confocal Microscopy and FRET

Fluorescent gold nanoclusters (AuNCs) capped with lysozymes are used to deliver the anticancer drug doxorubicin to cancer and noncancer cells. Doxorubicin‐loaded AuNCs cause the highly selective and efficient killing (90 %) of breast cancer cells (MCF7) (IC₅₀=155 nm ). In contrast, the killing of the noncancer breast cells (MCF10A) by doxorubicin‐loaded AuNCs is only 40 % (IC₅₀=4500 nm ). By using a confocal microscope, the fluorescence spectrum and decay of the AuNCs were recorded inside the cell. The fluorescence maxima (at ≈490–515 nm) and lifetime (≈2 ns), of the AuNCs inside the cells correspond to Au_10–13. The intracellular release of doxorubicin from AuNCs is monitored by Förster resonance energy transfer (FRET) imaging.     

The inhibition profiles of 4'-acylpyrrole–5-fluoroindolin-2-ones with a C-3' side chain for VEGFR2, PDGFR-β, and FGFR-1 protein kinases

In this study, we reported the inhibition profiles of 4′-acylpyrrole–5-fluoroindolin-2-one 3 with a C-3′ side chain for VEGFR2, PDGFR-β, and FGFR-1 protein kinases. The pyrrole-fused cyclohexanone moiety provided 3 with the best potency to inhibit the three kinases, and the C-3′ side chains contributed to the different inhibition profiles of 3 . Compound 3b with a C-3′ 2-carboxylethyl side chain showed good potency for the three kinase (IC₅₀: 25–260 nM), and compound 3g with a N,N-dialkyl-2-carbamoylethyl side chain was more active for VEGFR2 (IC₅₀: 59 nM) and PDGFR-β (IC₅₀: 16 nM) than FGFR-1 (IC₅₀: 1.7 μM). The C-3′ 3-(dialkylamino)propyl side chain accomplished 3h – j as selective PDGFR-β inhibitors (IC₅₀: 7.8–13 nM). Compound 3b was further investigated and found potent to inhibit VEGF- and FGF-dependent cell proliferation with moderate in vivo anticancer activity. Results from docking simulations revealed that the interactions of 3b with VEGFR2 and FGFR-1 which could account for the different inhibition profiles of 3 .     

A Reversible and Selective Inhibitor of Monoacylglycerol Lipase Ameliorates Multiple Sclerosis

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2‐arachidonoylglycerol (2‐AG). MAGL inhibitors show analgesic and tissue‐protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC₅₀=0.18 μM ) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB₁‐mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.     

Synthesis of 4‐alkyl‐1,2‐diphenyl‐3,5‐dioxopyrazolidines possessing aryl methylsulfonyl and sulfonamide pharmacophores for evaluation as selective cyclooxygenase‐2 (COX‐2) inhibitors

A group of 1,2‐diphenyl‐3,5‐dioxopyrazolidines possessing a methylsulfonyl ( 11 ) or sulfonamide ( 15 ) substituent at the para position of the N¹‐phenyl ring, in conjunction with a hydrogen, methyl or fluoro sub‐stituent at the para position of the N²‐phenyl ring, and a C‐4 n‐butyl, methyl or spiro‐cyclopropyl substituent were synthesized for evaluation as potential cyclooxygenase‐2 (COX‐2) selective inhibitor antiinflammatory agents. The title compounds 11 and 15 were synthesized using a four‐step and a three‐step reaction sequence, respectively. Thus, the acetic acid promoted condensation of a nitrosobenzene 5 with an aniline derivative ( 6, 12 ) gave the corresponding azobenzene product ( 8, 13 ) which was reduced with zinc dust in the presence of ammonium chloride to yield the corresponding hydrazobenzene ( 9, 14 ). Base‐catalyzed condensation of 9 and 14 with a malonyl dichloride ( 10 ) afforded the target 3,5‐dioxopyrazolidine product ( 11,15 ). 4‐n‐Butyl‐1‐(4‐methylsulfonylphenyl)‐2‐phenyl‐3,5‐dioxopyrazolidine ( 11a ) was a selective COX‐1 inhibitor (COX‐1 IC₅₀ = 8.48 μM). In contrast, 4‐n‐butyl‐1‐(4‐methylsulfonylphenyl)‐2‐(4‐tolyl)‐3,5‐dioxopyrazolidine ( 11b , COX‐2 IC₅₀ = 11.45 μM) and 4‐n‐butyl‐1‐(4‐methylsulfonylphenyl)‐2‐(4‐fluorophenyl)‐3,5‐dioxopyrazoli‐dine ( 11c , COX‐2 IC₅₀ = 9.86 μM) were about 46‐fold and 20‐fold less selective COX‐2 inhibitors respectively, relative to the reference drug celecoxib.     

A Potent,Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)

PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell‐active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure‐based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC₅₀=31±2 nM , K_D=53±2 nM ) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non‐epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3‐SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well‐characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.     

A Potent,Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)

PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell‐active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure‐based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC₅₀=31±2 nM , K_D=53±2 nM ) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non‐epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3‐SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well‐characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.     

Design,Synthesis, and Thrombin Inhibitory Activity Evaluation of Some Novel Benzimidazole Derivatives

Some benzimidazole derivatives were designed and screened via molecular docking. Six compounds which obtained high scores were selected for synthesis and all compounds were characterized by ¹H‐ and ¹³C‐NMR, and HR‐ESI‐MS. Subsequently, these compounds were evaluated for their inhibitory activities on thrombin. Compound 5a (IC₅₀ 3.11 nm ) showed a better activity than the reference argatroban (IC₅₀ 9.88 nm ). These results, along with related molecular model studies, indicated that 5a could be a potential thrombin inhibitor for further research.     

Design and Synthesis of Novel Pyrazole‐based Lp‐PLA2 Inhibitors

A series of novel pyrazole‐based lipoprotein‐associated phospholipase A₂ (Lp‐PLA₂) inhibitors have been designed and synthetized by a variety of acetophenones via a 10‐step convergent approach. The synthetic approach is carefully optimized, and an unsuccessful alternative route is also discussed. The in vitro biological activity reveals that all the synthesized compounds are potent Lp‐PLA₂ inhibitors with compound 13b being the most potent one (Lp‐PLA₂, IC₅₀=1.5 nmol/L).     

Synthesis,Biological Evaluation,and Molecular Docking Studies of Novel Pyrazolo[3,4‐d]pyrimidines as Potential Telomerase Inhibitors

Series of novel pyrazolo[3,4‐d]pyrimidines as potential telomerase inhibitors were synthesized. Results of the antitumor assay indicated that compounds 4b , 5a – b , 13b , c , and 14a , b exhibited the most potent activity (IC₅₀ from 39 to 43 μM) against Ehrlich ascites carcinoma cells (EAC). Also, the newly synthesized compounds were examined for telomerase inhibition by the known a TRAP assay. The results showed that compound 13c has remarkable inhibition activity with IC₅₀ value of 30 μM. On the other hand, computational studies were performed to the titled compounds to get insight in their degree of recognition with the conserved amino acids of the telomerase enzyme active site (code: 3DU6) as promising lead in the cancer cure era.     

Nitrosopurines En Route to Potently Cytotoxic Asmarines

A nitrosopurine ene reaction easily assembles the asmarine pharmacophore and transmits remote stereochemistry to the diazepine‐purine hetereocycle. This reaction generates potent cytotoxins which exceed the potency of asmarine A (1.2 μM IC₅₀) and supersede the metabolites as useful leads for biological discovery.     

Synthesis and antitumor activity of novel phenylhydrazonopyrazolone derivatives and molecular dynamics simulations

SHP2 is a new promising target for anti-cancer drug discovery. A series of novel phenylhydrazonopyrazolone derivatives was synthesized by a more convenient method, and their chemical structures were characterized by various spectroscopic methods. The inhibitory effects of these compounds on SHP2 enzyme and SHP2-dependent cancer cell H1975 were evaluated. The compound 11f with IC₅₀ value of 3.38 μmol/L exhibited more potent antitumor activity against H1975 cell than GS-493 (IC₅₀?=?20.92 μmol/L). Molecular dynamics simulation of compound 11f displayed a possible mode of interaction between this compound and SHP2 enzyme.     

Synthesis and evaluation of new pyrazoline‐thiazole derivatives as monoamine oxidase inhibitors

A novel series of 1,3,5‐trisubstituted‐2‐pyrazoline derivatives ( 4a ‐ 4k ) was synthesized and their chemical structures characterized by ¹H NMR, ¹³C NMR, and mass spectroscopy. These compounds were evaluated as inhibitors for of type A and type B monoamine oxidase (MAO) enzymes. The most common inhibitors of MAO enzymes used to treat depression and anxiety such as selegiline and moclobemide drugs were used as reference agents. A result of biological evaluation of these compounds revealed compounds 4c , 4d , and 4? as potent and selective MAO A inhibitors. The most active compound 4? , which is 2,4‐dimethoxy at phenyl ring, showed strong inhibitory activity at MAO A (IC₅₀ of 0.0445 ± 0.0018μM). Furthermore, compounds 4c and 4d showed significant inhibition profile on MAO A with the IC₅₀ values 0.1423 ± 0.0051μM and 0.2148 ± 0.0067μM, respectively.     

Synthesis of spirooxindoles promoted by the deep eutectic solvent,ZnCl2+urea via the pseudo four-component reaction: anticancer,antioxidant, and molecular docking studies

Abstract

Various spirooxindoles (7a–c, 8a–c, 9a–c, and 10a–c) were efficiently synthesized using deep eutectic solvent ZnCl₂+urea and well characterized using IR, ¹H NMR, and ¹³C NMR spectroscopic techniques. The biological screening results showed that the compound 9a exhibited potent anticancer activity against MCF7 and HeLa cell lines with IC₅₀ values 6.47?±?0.01 and 9.14?±?0.32?µM, respectively. The compound 7c exhibited potent activity against the HeLa cell line with IC₅₀ value 6.81?±?0.01?µM. The compound 9a exhibited a potent antioxidant activity with IC₅₀ value 7.34?±?0.17?µM. The comparative molecular docking study against the cancer proteins EGFR and HER2 revealed that the EGFR was the best target protein receptor for the target compounds. Among all the compounds, the compound 9a exhibited the least binding energy ?10.72?kcal/mol against the protein EGFR (PDB ID: 4HJO).     

Evaluation of newly synthesized derivatives of bis(hydrazine‐1‐carbothioamide) and their metal complexes synthesized in bulk and nano size as potent anticancer agents

A series of new metal complexes were synthesized in both bulk and nano size using green methods, starting with the reaction of (E)‐N′‐[(E)‐2‐bromobenzylidene]‐4‐oxo‐4‐(piperidin‐1‐yl)but‐2‐enehydrazide with thiosemicarbazide and different metal halides such as CuI·2H₂O, CuCl₂·2H₂O, CoCl₂·2H₂O, and ZnCl₂·2H₂O, and metal nitrate such as Ga(NO₃)₃·2H₂O. Structures of these metal complexes were confirmed using different spectroscopic methods, elemental analysis, electronic spectra, and microanalytical methods (scanning electron microscopy and transmission electron microscopy) for nano complexes. The distorted octahedral geometry for all complexes was suggested based on magnetic moments and electronic spectral studies. The cytotoxic activity of the compounds was investigated against human hepatocellular carcinoma (HepG2) and human colorectal carcinoma (HCT‐116) cell lines. Most tested compounds had higher inhibitory activity than the standard vinblastine drug. Interestingly, the nano‐sized Ga(III) complex 11 was the most potent compound against the two tested cell lines, with 50% inhibitory concentration (IC₅₀) of 2.56 μg/mL for HepG2, compared with the reference drug vinblastine (IC₅₀ 15.6 μg/mL), and IC₅₀ 4.64 μg/mL for HCT‐116, compared with the standard (IC₅₀ 13.9 μg/mL). The bioassay results helped us identify new potent and selective anticancer agents.     

Inhibitors of the Bifunctional 2‐C‐Methyl‐d‐erythritol 4‐Phosphate Cytidylyl Transferase/2‐C‐Methyl‐d‐erythritol‐2,4‐cyclopyrophosphate Synthase (IspDF) of Helicobacter pylori

A library of over 103 thousand compounds was screened for inhibitors of the IspD domain (2‐C‐methyl‐d ‐erythritol 4‐phosphate cytidylyl transferase domain) of the bifunctional IspDF protein from Helicobacter pylori using a photometric assay. Around 300 compounds showed IC₅₀ values below 100 μm , and three compounds had IC₅₀ values below 1 μm . A few IspD inhibitors could also inhibit the IspF domain (2‐C‐Methyl‐d ‐erythritol‐2,4‐cyclopyrophosphate synthase) of the IspDF protein. The most potent IspD inhibitors were tested as growth inhibitors of H. pylori. Several compounds showed inhibition of bacterial growth with IC₅₀ in the single‐digit μm range. The most potent growth inhibitor had an IC₅₀ value of 3.4 μm . The most potent growth inhibitor without measurable effect on eukaryotic cell viability had an IC₅₀ value of 7.2 μm .     

Synthesis of 4‐Heteroaryl–Quinazoline Derivatives as Potential Anti‐breast Cancer Agents

4‐Heteroaryl or heteroalkyl–quinazoline derivatives were prepared as dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibitors. The new compounds were tested for their dual enzyme inhibition as well as their cytotoxic activity on MCF7 cell line. The results indicated that almost all the compounds showed moderate dual inhibition of both enzymes. Compound 3 (methyl piperidine‐4‐carboxylate derivative) showed the highest inhibitory activity against both enzymes with IC₅₀ 97.6 and 64.0 µM against EGFR and VEGFR‐2 kinases, respectively. Most of the test compounds showed potent to moderate antitumor activity on MCF7 cell line. Five compounds ( 3 , 9c , 11 , 13 , and 15b ) showed potent cytotoxic activity with IC₅₀ values between 10 and 17 µM .     

Ciprofloxacin/Gatifloxacin‐1,2,3‐triazole‐isatin Hybrids and Their In Vitro Anticancer Activity

Eleven novel ciprofloxacin/gatifloxacin‐1,2,3‐triazole‐isatin hybrids ( 8a – k ) were designed, synthesized, and screened for their in vitro anticancer activity in this paper. A significant part of the synthesized hybrids was active against A549, HepG2, and SF‐268 cancer cell lines, whereas the parent drugs ciprofloxacin and gatifloxacin were devoid of activity. Among them, hybrid 8i (IC₅₀: 78.1–90.7 μM) was found to be the most active against A549, HepG2, and SF‐268 cancer cell lines, and it was comparable with or better than Vorinostat (IC₅₀: 71.1 to >100 μM). Thus, these kind hybrids have potentiality for discovery of new anticancer candidates for clinical deployment in the control and eradication of cancers.     

Microwave‐Assisted Synthesis and Antituberculosis Screening of Some 4‐((3‐(Trifluoromethyl)‐5,6‐dihydro‐[1,2,4]triazolo[4,3‐a]pyrazin‐7(8H)‐l)methyl)benzenamine Hybrids

In the present investigation, a series of 4‐((3‐(trifluoromethyl)‐5,6‐dihydro‐[1,2,4]triazolo[4,3‐a]pyrazin‐7(8H)‐yl)methyl)benzenamine analogs 6a–o were synthesized and characterized by IR, NMR (¹H and ¹³C), and mass spectra. All newly synthesized compounds 6a–o were prepared under conventional and microwave irradiation methods. These compounds obtained in higher yields and in shorter reaction times in the microwave irradiation method when compared with the conventional method. Synthesized compounds 6a–o were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Ra using an established XTT reduction menadione assay. Among the screened compounds, 6i (IC₅₀: 1.82 μg/mL), 6j (IC₅₀: 1.02 μg/mL), and 6k (IC₅₀: 1.59 μg/mL) showed excellent activity. Furthermore, compound 6i showed MIC₉₀ value of 16.02 μg/mL. In summary, the results indicate the identification of some novel, selective, and specific inhibitors against M. tuberculosis that can be explored further for the potential antitubercular drug.     

Collective Synthesis of 4‐Hydroxy‐2‐pyridone Alkaloids and Their Antiproliferation Activities

A collective synthesis of 4‐hydroxy‐2‐pyridone alkaloids—specifically, pretenellin B, prebassianin B, farinosone A, militarione D, pyridovericin, and torrubiellone C—has been achieved. Key steps include using a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki–Miyaura cross‐coupling reaction, a divergent synthesis approach of target molecules by aldol condensation of pyridone intermediate with homologous aldehydes, and an iterative synthesis of homologous aldehydes with all‐trans‐polyene backbones. Interestingly, among the six tumor cell lines investigated, torrubiellone C was found to induce potent and apoptotic inhibitory activities on Jurkat T cells with IC₅₀ values of 7.05 μM . Hence, this approach could potentially contribute to the synthesis of bioactive small‐molecule libraries as well as drug discovery.