Novel α,β-unsaturated hydroxamic acid derivatives overcome cisplatin resistance

A series of α,β-unsaturated hydroxamic acid derivatives as novel HDAC inhibitors (HDACi) with structural modifications of the connecting unit and the CAP group was synthesized. The in vitro evaluation against the human cancer cell lines A2780 and Cal27 identified 6e and 7j as the most potent compounds regarding HDAC inhibitory activity and inhibition of proliferation. Isoform profiling against HDAC2, 4, 6 and 8 revealed a preference for HDAC2 and 6 for both compounds in contrast to the pan HDACi panobinostat. 6e and 7j enhanced significantly cisplatin-induced cytotoxicity in a combination treatment mediated by increased apoptosis induction and caspase-3/7 activation. The interaction between 6e or 7j and cisplatin was highly synergistic and more pronounced for the cisplatin resistant subline Cal27CisR. IC₅₀ values of cisplatin were even lower in Cal27CisR pretreated with 6e or 7j than for the parental cell line Cal27. Based on our findings, the novel dual class I/HDAC6 inhibitors could serve as an option to overcome cisplatin resistance with fewer side effects in comparison to panobinostat.     

Synthesis of new simplified hemiasterlin derivatives with α,β-unsaturated carbonyl moiety

In this Letter, we report a convenient and efficient method for the synthesis of new simplified derivatives of hemiasterlin in which the α,α-dimethylbenzylic moiety A is replaced by α,β-unsaturated aryl groups as Michael acceptor. Most of these derivatives have a strong cytotoxic activity on three human tumor cell lines (KB, Hep-G₂ and MCF₇). Analogs 17b and 17f showed a high cytotoxicity against KB and Hep-G₂ cancer cell lines comparable to paclitaxel and ellipticine.     

Synthesis and biological evaluation of α,β-unsaturated lactones as potent immunosuppressive agents

Compounds having α,β-unsaturated lactones display a variety of biological activities. Many research groups have tested both natural and unnatural α,β-unsaturated lactones for as-yet undiscovered biological properties. We synthesized α,β-unsaturated lactones with various substituents at the δ-position and studied their immunosuppressive effects, that is, the inhibition of Interleukin-2 (IL-2) production. Among the compounds synthesized, the benzofuran-substituted α,β-unsaturated lactone 4h showed the best inhibitory activity toward IL-2 production in Jurkat e6-1 T lymphocytes (IC(50)=66.9 nM) without cytotoxicity at 10 μM. The results indicated that 4h may be useful as a potent immunosuppressive agent, as well as in IL-2-related studies.     

Design, synthesis and biological evaluation of new arylpiperazine derivatives bearing a flavone moiety as α1-adrenoceptor antagonists

Elaborate study on the three-dimensional model of α₁-adrenoceptor (α₁-AR) antagonists led to the development of a series of new arylpiperazine derivatives bearing a flavone nucleus as α₁-AR antagonists. The in vitro activities were evaluated and compounds 1, 4, 10, 13 and 15 showed activities close to the reference compound (Prazosin).     

Novel imino sugar α-glucosidase inhibitors as antiviral compounds

Deoxynojirimycin (DNJ) based imino sugars display antiviral activity in the tissue culture surrogate model of Hepatitis C (HCV), bovine viral diarrhoea virus (BVDV), mediated by inhibition of ER α-glucosidases. Here, the antiviral activities of neoglycoconjugates derived from deoxynojirimycin, and a novel compound derived from deoxygalactonojirimycin, by click chemistry with functionalised adamantanes are presented. Their antiviral potency, in terms of both viral infectivity and virion secretion, with respect to their effect on α-glucosidase inhibition, are reported. The distinct correlation between the ability of long alkyl chain derivatives to inhibit ER α-glucosidases and their anti-viral effect is demonstrated. Increasing alkyl linker length between DNJ and triazole groups increases α-glucosidase inhibition and reduces the production of viral progeny RNA and the maturation of the envelope polypeptide. Disruption to viral glycoprotein processing, with increased glucosylation on BVDV E2 species, is representative of α-glucosidase inhibition, whilst derivatives with longer alkyl linkers also show a further decrease in infectivity of secreted virions, an effect proposed to be distinct from α-glucosidase inhibition.     

Schiff’s base derivatives bearing nitroimidazole moiety: New class of antibacterial,anticancer agents and potential EGFR tyrosine kinase inhibitors

New Schiff’s base derivatives 5a–5h have been synthesized by reaction between 1-(4-bromophenyl)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanone 3 and various benzohydrazide 4a–4h in presence of nickel (II) nitrate as a catalyst in ethanol at room temperature in good yield (54–88%). All compounds were tested for antibacterial as well as anticancer and inhibition of EGFR. Of the compounds studied, compounds 5d, 5f and 5g in the case of antiproliferation and inhibition of EGFR as well as compounds 5b, 5c, 5e and 5h in the case of antibacterial activity were found to be most effective compounds in the series. Compound 5f shows effective inhibition (IC₅₀ = 0.21 ± 0.02 μM) by binding in to the active pocket of EGFR receptor with minimum binding energy (ΔG_b = ?49.4869 kcal/mol).     

Novel cycloalkylthiophene–imine derivatives bearing benzothiazole scaffold: Synthesis,characterization and antiviral activity evaluation

A series of novel cycloalkylthiophene–imine derivatives containing benzothiazole unit were designed, synthesized and evaluated for their anti-viral activities. The bio-evaluation results indicated that some of the target compounds (such as 5g, 5i, 5u) exhibited good to moderate antiviral effect on CVB5, ADV7 and EV71 viruses, however, these compounds did not have inhibition activity against H1N1 virus. Especially, the compounds 4c and 4d also exhibited high antiviral activities, which provide a new and efficient approach to evolve novel multi-functional antiviral agents by rational integration of active pharmacophores.     

Design and synthesis of γ-butyrolactone derivatives as potential spermicidal agents

A series of γ-butyrolactone derivatives has been designed and synthesized from commercially available 2-acetyl butyrolactone (3-acetyldihydrofuran-2(3H)-one, 1) by aminoalkylating its active methylene followed by condensation with different aldehydes. Compounds having amino group were further converted to their respective tartrate salts and were evaluated for spermicidal activity against human sperm in vitro. Compounds showing appreciable spermicidal activity at ⩽0.5% [3c, 4d (0.5%); 2c, 3d (0.1%); 2d, 4c (0.05%)] were tested for safety studies against human cervical (HeLa) cell line. These compounds were found safer than, Nonoxynol-9. One of the two most active compounds was also found to be the safest (IC₅₀ = 961 μg/ml; 4c), while the second compound exhibited lower safety against HeLa (IC₅₀ = 269 μg/ml; 2d). The compound 4c significantly reduced the number of free thiols on human sperm. All the compounds were inactive against Trichomonas vaginalis.     

A novel piperazine linked β-amino alcohols bearing a benzosuberone scaffolds as anti-proliferative agents

A new series of 1-((9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methoxy)-3-(4-phenylpiperzin-1-yl) propan-2-ols (6a-k) have been designed, synthesized and their structures were established by spectroscopic data (FT-IR, ¹H NMR, ¹³C NMR, HRMS) and further confirmed by X-ray analysis. The newly synthesized compounds 6a-k were evaluated for their in vitro anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MDA-MB-231 (breast), A549 (lung) and MIAPACA (pancreatic). Among the compounds tested, the compound 6e displayed most potent activity against four cancer cell lines with GI₅₀ values ranging from 0.010 to 0.097 μM. The structure and anti-proliferative activity relationship was further supported by in silico molecular docking study of the active compounds against Colchicine binding site of β-tubulin.     

Helix induction potential of N-terminal α-methyl, α-amino acids

Summary A series of longer analogues of the C-peptide of RNAse A has been synthesized with the aim of assessing the helix induction potential in water of α-methyl, α-amino acids at the N-terminus of the chain. The circular dichroism data indicate that one isovaline residue is effective in increasing the helix content of the 13-residue peptide by about 7%.     

Synthesis and in vitro evaluation of antimycobacterial and cytotoxic activity of new α,β-unsaturated amide,oxazoline and oxazole derivatives from l-serine

The synthesis of 19 compounds derived from l-serine and analogs of p-substituted cinnamic acid is reported. Oxazolines 9 and oxazoles 10 have high antitubercular activity with Minimum Inhibitory Concentration (MIC) of 0.7812–25.0 µg/mL (3.21–100.3 µM), against two strains of Mycobacterium tuberculosis sensitive to first-line drugs Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB), Pyrazinamide (PZE) (H37Rv) and a clinical isolate resistant to INH, RIF and EMB (G122). The cytotoxic evaluation shows that oxazoles have low activity, finding viability>96% against the VERO cell line. The results show these compounds could be considered as future alternatives for antitubercular treatment.     

Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents

A series of new 4β-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the compounds exhibited better growth-inhibition activities against tested cell lines than that of etoposide. Further, compounds 6g and 6i are also evaluated for their DNA topoisomerase-II (topo-II) inhibition activity and they exhibited significant inhibition of topo-II catalytic activity comparable to etoposide.     

New benzyl pyridinium derivatives bearing 2,4-dioxochroman moiety as potent agents for treatment of Alzheimer’s disease: Design,synthesis, biological evaluation,and docking study

A new series of benzyl pyridinium-2,4-dioxochroman derivatives 7a-o was synthesized and evaluated as new anti-Alzheimer agents. Among the synthesized compounds, the compounds 7f and 7i exhibited the most potent anti-AChE and anti-BuChE activities, respectively. The kinetic study of the compound 7f revealed that this compound inhibited AChE in a mixed-type inhibition mode. Furthermore, the docking study of the compounds 7f and 7i showed that these compounds bound to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE, respectively. The compound 7f also exhibited a greater self-induced Aβ peptide aggregation inhibitory activity in compare to donepezil. Furthermore, the neuroprotective activity of this compound at 20 μM was comparable to that of the standard neuroprotective agent (quercetin).     

Tetrahydroacridine derivatives with fluorobenzoic acid moiety as multifunctional agents for Alzheimer’s disease treatment

A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 2-fluorobenzoic acid or 3-fluorobenzoic acid moiety were designed, synthesized and evaluated as inhibitors of cholinesterases and aggregation of β-amyloid. In the study target compounds were very potent inhibitors of AChE and BChE. The most promising agents had higher inhibitory potency than the reference drugs which was tacrine. Ultimately, the kinetic assay shows the most active target compound 3c against AChE. Almost all of them were more potent against BChE than AChE. Compound 3c in various concentrations was tested by aggregation experiment. Inhibition of β-amyloid aggregation was 77.32% and 80.43% at 50 µM and 100 µM, respectively. Therefore, compound 3c is a promising agent for the treatment of AD.     

Synthesis,antimycobacterial and cytotoxic activity of α,β-unsaturated amides and 2,4-disubstituted oxazoline derivatives

The synthesis of six α,β,-unsaturated amides and six 2,4-disubstituted oxazolines derivatives and their evaluation against two Mycobacterium tuberculosis strains (sensitive H37Rv and a resistant clinical isolate) is reported. 2,4-Disubstituted oxazolines (S)-3b,d,e were the most active in the sensitive strain with a MIC of 14.2, 13.6 and 10.8 μM, respectively, and the compounds (S)-3d,f were the most active against resistant strain with a MIC of 6.8 and 7.4 μM. The ex-vivo evaluation of hepatotoxicity on precision-cut rat liver slices was also tested for the α,β-unsaturated amides (S)-2b and (S)-2d,f and for the oxazolines (S)-3b and (S)-3d,f at different concentrations (5, 15 and 30 μg/mL). The results indicate that these compounds possess promising antimycobacterial activity and at the same time are not hepatotoxic. These findings open the possibility for development of new drugs against tuberculosis.     

Routes to higher-carbon sugar derivatives having keto-acetylenic and -alkenic,and α,β-unsaturated aldehyde functionality

Oxidative dimerization of 7,8-dideoxy-1,2:3,4-di-O-isopropylidene-d-glycero-α-d-galacto-oct-7-ynopyranoside (1) gave a high yield of the diyne 2, readily reduced by lithium aluminum hydride to the trans,trans-diene (4). The structures of 2 and 4 were established spectroscopically and by degradation of 4 to d-glycero-d-galacto-heptitol (perscitol). A mixture of the alkyne 1 and its 7-epimer 10 was readily oxidized by dimethyl sulfoxide-acetic anhydride to the 6-ketone 11, and the 8-alkene analog was similarly prepared from the alkenes derived from 1 and 10. Likewise, oxidation of 6,7-dideoxy-1,2-O-isopropylidene-α-d-gluco(and β-L-ido)-hept-6-enopyranose gave the corresponding 5-ketone. The acetylenic ketone 11 gave a crystalline oxime and (2,4-dinitrophenyl)hydrazone, the latter being accompanied by the product of attack of the reagent at the acetylene terminus (C-8). Previous work had shown that formyl-methylenetriphenylphosphorane did not convert 1,2:3,4-di-O-isopropylidene-6-aldehydo-α-d-galacto-hexodialdo-1,5-pyranose into the corresponding C₈ unsaturated aldehyde, although the latter was obtainable via1 and 10 by an ethynylation-hydroboration sequence. The Wittig route with formylmethylenetriphenylphosphorane is shown to be satisfactory for obtaining C₇ unsaturated aldehydes from 3-O-benzyl-1,2-O-isopropylidene-5-aldehydo-α-d-xylo-pentodialdo-1,4-furanose (22) and the 3-epimer of 22, respectively. These reactions provide convenient access to higher-carbon sugars and chiral dienes for synthesis of optically pure products of cyclo-addition reactions.     

Design,synthesis and evaluation of pterostilbene β-amino alcohol derivatives as multifunctional agents for Alzheimer's disease treatment

A series of pterostilbene β-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC₅₀ = 24.04 μM), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H₂O₂-induced PC-12 cell injury. Moreover, 5f also showed self-induced Aβ_1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro. These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD.     

Novel anilinophthalimide derivatives as potential probes for β-amyloid plaque in the brain

A group of novel 4,5-dianilinophthalimide derivatives has been synthesized in this study for potential use as β-amyloid (Aβ) plaque probes. Staining of hippocampus tissue sections from Alzheimer’s disease (AD) brain with the representative compound 9 indicated selective labeling of it to Aβ plaques. The binding affinity of radioiodinated [¹²⁵I]9 for AD brain homogenates was 0.21 nM (K_d), and of other derivatives ranged from 0.9 to 19.7 nM, except for N-methyl-4,5-dianilinophthalimide (K_i > 1000 nM). [¹²⁵I]9 possessed the optimal lipophilicity with Log P value of 2.16, and its in vivo biodistribution in normal mice exhibited excellent initial brain uptake (5.16% ID/g at 2 min after injection) and a fast washout rate (0.56% ID/g at 60 min). The encouraging results suggest that this novel derivative of [¹²³I]9 may have potential as an in vivo SPECT probe for detecting amyloid plaques in the brain.     

Discovery of γ-lactam derivatives containing 1,3-benzodioxole unit as potential anti-phytopathogenic fungus agents

A series of γ-lactam analogs containing 1,3-benzodioxole moiety were designed, and these derivatives were synthesized from the lead compound of lactam via a structural diversity-oriented synthesis, their structures were confirmed by ¹HNMR,¹³CNMR, ESI-MS spectrum. Their antifungal activities were evaluated against four serious and typically crop-threatening agricultural fungi, including Rhizoctonia solani, Alternaria tenuis Nees, Gloeosporium theae-sinensis, and Fusarium graminearum. Some of these derivatives exhibited activity against Alternaria tenuis Nees higher than that of commercial fungicides carbendazim, such as compounds 7a, 7b, and 7i, compared with the blank control, some of these derivatives showed good antifungal activities against Gloeosporium theae-sinensis and Fusarium graminearum. The systematic study provides evidences for further structural modification and application of lactam analogues as antifungal agents for agriculture.     

Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents

N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.