Synthesis and biological evaluation of novel C6-amino substituted 4-azasteroidal purine nucleoside analogues

Novel C6-amino substituted purine nucleoside analogues (2–12) bearing a modified pyranose-like D ring of the 4-azasteroid moiety were efficiently synthesized through nucleophilic substitution at C6 position of the steroidal nucleoside precursors (1a, b) with versatile amines. All the synthesized new compounds were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines. Among them, compounds 4b, 7b and 9b exhibited significant cytotoxicity with the IC₅₀ values of 2.99 μM (PC-3), 2.84 μM, (PC-3) and 2.69 μM (Hela), respectively.     

Synthesis and antimicrobial evaluation of some new substituted purine derivatives

A series of 8,9-disubstituted adenines (4, 5, 8), 6-substituted aminopurines (10–13) and 9-(p-fluorobenzyl/cyclopentyl)-6-substituted aminopurines (16, 17, 19–30) have been prepared and the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA, standard and clinical isolate), Bacillus subtilis, Escherichia coli and Candida albicans were evaluated. 6-[(N-phenylaminoethyl)amino]-9H-purine (12) which has no substitution at N-9 position and 9-cyclopentyl-6-[(4-fluorobenzyl)amino]-9H-purine (24) exhibited excellent activity against C. albicans with MIC 3.12 μg/mL. These compounds displayed better antifungal activity than that of standard oxiconazole. Furthermore, compound 22 carrying 4-chlorobenzylamino group at the 6-position of the purine moiety exhibited comparable antibacterial activity with that of the standard ciprofloxacin against both of the drug-resistant bacteria (MRSA, standard and clinical isolate).     

Synthesis and biological evaluation of novel daunorubicin-estrogen conjugates

The synthesis of two novel daunorubicin-estrogen conjugates with a steroidal and a non-steroidal ligand was undertaken in an attempt to target the cytotoxicity of anthracycline to estrogen-receptor positive cells. These conjugates (3 and 4), in contrast to their corresponding ligands, displayed weak binding affinities of 0.079 and 0.851 for the estrogen receptor. Conjugate 3 was consistently more cytotoxic than 4, which however showed some selectivity to estrogen receptor positive cell lines.     

Synthesis and bradykinin inhibitory activity of novel non-peptide compounds,and evaluation of in vivo analgesic activity

A series of novel non-peptide diamide compounds was synthesized and evaluated as antibradykinin agents by utilizing guinea-pig ileum smooth muscle. Among the final compounds, (Z)-4-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-4-oxo-N-(4-phenylbutan-2-yl)but-2-enamide showed most favorable bradykinin inhibitory activity and demonstrated analgesic efficacies in the rat models of inflammatory and neuropathic pain.     

Synthesis and antiproliferative activity of novel steroidal dendrimer conjugates

We describe the synthesis of steroidal dendrimer conjugates of first and second generation with tetramethylene core and 5-hydroxy-isophtalic acid dimethyl ester as branching unit modified to incorporate ethynylestradiol or 17α-estradiol as terminal units. The steroidal dendrimer conjugates, the free drug (steroids) and dendrimer were tested against a panel of cancer cell lines (CEM, MCF7, HeLa) and normal human fibroblast (BJ). The steroidal dendrimer conjugates of first generation exhibited cytotoxic activity and induced apoptosis in chronic leukemia (CEM) as resultant activation of caspase cascade which is mainly provoked in G2/M arrested cells.     

Synthesis and evaluation of uterine relaxant activity for a novel series of substituted p-hydroxyphenylethanolamines

Novel racemic 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl]aminopropan-1-ol hydrochlorides (9a-h) were synthesized by condensing racemic 1-(p-hydroxyphenyl)-2-aminopropan-1-ol hydrochloride (6) with substituted aryloxymethyloxiranes (8a-h) in DMF in presence of anhydrous potassium carbonate and then reacting with dry hydrogen chloride gas. They were evaluated for uterine relaxant activity in vitro on isolated rat uterus and in vivo in pregnant rats. Their cAMP releasing potential was studied using rat uterus tissue homogenates by cAMP [3H] assay and cardiac stimulant potential was evaluated in dog. All compounds exhibited potent uterine relaxant activity in vitro and produced a significant delay in the onset of labour in pregnant rats; their cAMP releasing potential was higher than isoxsuprine hydrochloride except for 9b and 9c. Finally insignificant cardiac stimulant potential was noted for these compounds when compared to isoxsuprine hydrochloride.     

Synthesis and biological in vitro evaluation of novel PEG-psoralen conjugates

Psoralens are well-known photosensitizers, and 8-methoxypsoralen and 4,5',8-trimethylpsoralen are widely used in photomedicine as "psoralens plus UVA therapy" (PUVA), in photopheresis, and in sterilization of blood preparations. In an attempt to improve the therapeutic efficiency of PUVA therapy and photopheresis, four poly(ethylene glycol) (PEG)-psoralen conjugates were synthesized to promote tumor targeting by the enhanced permeability and retention (EPR) effect. Peptide linkers were used to exploit specific enzymatic cleavage by lysosomal proteases. A new psoralen, 4-hydroxymethyl-4',8-dimethylpsoralen (6), suitable for polymer conjugation was synthesized. The hydroxy group allowed exploring different strategies for PEG conjugation, and linkages with different stability such ester or urethanes were obtained. PEG (5 kDa) was covalently conjugated to the new psoralen derivative using four different linkages, namely, (i) direct ester bond (7), (ii) ester linkage with a peptide spacer (8), (iii) a carbamic linker (9), and (iv) a carbamic linker with a peptide spacer (12). The stability of these new conjugates was assessed at different pHs, in plasma and following incubation with cathepsin B. Conjugates 7 and 8 were rapidly hydrolyzed in plasma, while 9 was stable in buffer and in the presence of cathepsin B. As expected, only the conjugates containing the peptide linker released the drug in presence of cathepsin B. In vitro evaluation of the cytotoxic activity in the presence and absence of light was carried out in two cell lines (MCF-7 and A375 cells). Conjugates 7 and 8 displayed a similar activity to the free drug (probably due to the low stability of the ester linkage). Interestingly, the conjugates containing the carbamate linkage (9 and 12) were completely inactive in the dark (IC50 > 100 microM in both cell lines). However, antiproliferative activity become apparent after UV irradiation. Conjugate 12 appears to be the most promising for future in vivo evaluation, since it was relatively stable in plasma, which should allow tumor targeting and drug release to occur by cathepsin B-mediated hydrolysis.     

Synthesis and kinase inhibitory activity of novel substituted indigoids

The bis-indole indigoids are a promising protein kinase inhibitor scaffold to be further evaluated against the numerous human diseases that imply abnormal regulation of kinases including neurodegenerative disorders. In an effort to identify new pharmacological inhibitors of disease-relevant protein kinases with increased potency and selectivity, we designed, synthesized new 5,7-disubstituted or 6-substituted bis-indole derivatives. On the basis of our previous synthetic work, 22 selected compounds were tested on CDK1/cyclin B, CDK5/p25, DYRK1A, CK1, and GSK-3α/β kinases, five kinases involved in Alzheimer’s disease. Some of them were also evaluated for their cytotoxic and antiproliferative activities. 6-Nitro-3′-N-oxime-indirubin and 5-amino-3′-N-oxime-indirubin derivatives exhibited inhibitory activity in a submicromolar range against CDK1/cyclin B (0.18 and 0.1 μM, respectively), CK1 (0.6 μM and 0.13 μM) and GSK3 (0.04 μM and 0.36 μM).     

Synthesis and T-type calcium channel blocking activity of novel diphenylpiperazine compounds,and evaluation of in vivo analgesic activity

Novel diphenylpiperazine derivatives were synthesized and evaluated for their inhibitory activity against T-type calcium channel by whole-cell patch clamp recordings on HEK293 cells. Among the test compounds, 2 and 3d were effective in decreasing the response to formalin in both the first and second phases and demonstrated antiallodynic effects in a rat model of neuropathic pain.     

A novel ketolide class: Synthesis and antibacterial activity of a lead compound

Synthesis and antibacterial activity of a new class of ketolide antibiotics, exemplified by the prototype GW680788X (1), are described. The structure of (1) has been elucidated by spectroscopic analysis. The good antibacterial activity shown by (1) in comparison with clarithromycin prompted us to consider this compound as a lead molecule for further exploration.     

Synthesis and biological evaluation of arylphosphonium-benzoxaborole conjugates as novel anticancer agents

Arylphosphonium-benzoxaborole conjugates have been synthesized as potential mitochondria targeting anticancer agents. The synthesized compounds have been tested for their effects on cell viability in various solid tumor cell lines including breast cancer 4T1 and MCF-7, pancreatic cancer MIAPaCa-2 and colorectal adenocarcinoma WiDr. Compound 6c is designated as a lead compound for further studies due to its enhanced effects on cell viability in the above-mentioned cell lines. Seahorse Xfe96 based metabolic assays reveal that the lead candidate 6c inhibits mitochondrial respiration in 4T1 and WiDr cell lines as evidenced by the reduction of mitochondrial ATP production and increase in proton leak. Epiflourescent microscopy experiments also illustrate that 6c causes significant mitochondrial fragmentation in 4T1 and WiDr cells, morphologically consistent with programmed cell death. Our current studies illustrate that arylphosphonium-benzoxaborole conjugates have potential to be further developed as anticancer agents.     

Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates

A series of novel 1,3,4-oxadiazole/thiadiazole–chalcone conjugates were synthesized and their in vitro and in vivo antiviral activities were evaluated via microscale thermophoresis method and half-leaf method, respectively. The in vitro results indicated that compounds 7g, 7l, 8h, and 8l displayed good antiviral activity against TMV, with the binding constant values of 5.93, 6.15, 6.02, and 5.04 μM, respectively, which were comparable to that of Ninnanmycin (6.78 μM) and even better than that of Ribavirin (99.25 μM). The in vivo results demonstrated that compounds 7g, 7l, 8h, and 8l exhibited remarkable anti-TMV activity with the EC₅₀ values of 33.66, 33.97, 33.87 and 30.57 µg/mL, respectively, which were comparable to that of Ningnanmycin (36.85 µg/mL) and superior to that of Ribavirin (88.52 µg/mL). Interestingly, the trend of antiviral activity in vivo was consistent with the in vitro results.     

Synthesis and photodynamic activity of novel asymmetrically substituted fluorinated phthalocyanines

A series of asymmetrically substituted dodecafluorinated phthalocyanines has been synthesized via the Kobayashi ring expansion reaction of the corresponding dodecafluorinated boron subphthalocyanine with differently substituted 1,3-diiminoisoindolines. The mild reaction conditions employed during this ring expansion reaction gave rise exclusively to 3:1 asymmetrically substituted dodecafluorinated phthalocyanines. Metal insertion into the metal-free phthalocyanines was accomplished by heating at 40 degrees C in N,N-dimethylformamide in the presence of zinc bromide. The resulting zinc dodecafluorophthalocyanines were formulated as Cremophor EL oil-water emulsions and evaluated as photosensitizers in vitro against EMT-6 mouse mammary tumor cells. As compared to the previously studied zinc hexadecafluorophthalocyanine, these new asymmetrical zinc dodecafluorophthalocyanines exhibited improved photodynamic activity.     

Synthesis and antibacterial activity of novel fluoroquinolones containing substituted piperidines

The design and synthesis of new fluoroquinolone antibacterial agents having substituted piperidine rings at the C-7 position are described. Most of the new compounds demonstrated high in vitro antibacterial activity. Several of them exhibited significant activities against gram-positive organisms, which were more potent than those of gemifloxacin, Linezolid, and vancomycin.     

Genetic toxicity evaluation of McN-5195: A novel analgesic

McN-5195, (±)trans-3-(2-bromophenyl)octahydroindolizine, a novel analgesic, was tested for genotoxic potential in a battery of tests with endpoints of mutagenicity, chromosomal alterations and DNA damage/ repair. McN-5195 was not mutagenic when tested in the Ames test using strains TA98, TA100, TA1535, TA1537 and TA 1538, in the absence of metabolic activation and in the presence of Aroclor 1254-induced rat or hamster S-9. Negative results were also obtained in the mouse lymphoma assay in the absence of activation, but reproducible mutagenic responses were seen in this mammalian cell assay in the presence of rat S-9 at high levels of induced toxicity (reduced cell growth). Testing of the enantiomers of McN-5195 in this assay supported these findings. A predominance of small mutant colonies in the mouse lymphoma assay suggested a potential chromosomal effect of McN-5195. This was confirmed with positive findings in an in vitro cytogenetics assay using CHO cells, again at toxic exposure levels and only in the presence of S-9. McN-5195 did not induce DNA repair in the primary rat hepatocyte/DNA repair assay, nor did it induce alterations in vivo of chromosome structure or number when tested in a rat bone marrow cytogenetics assay. The findings from this battery of tests indicate that McN-5195 has modest genotoxic activity when tested in the presence of rat liver S-9 in in vitro systems sensitive to cytogenetic change. The absence of genotoxicity in vitro in Salmonella and intact liver cells and in vivo in rat bone marrow suggests that McN-5195 is unlikely to present a genotoxic risk to whole animals.Abbreviations 2-AA 2-anthramine - 9-AA 9-aminoacridine HCI - 2-AAF 2-acetylaminofluorene - AO acridine orange - CHO Chinese hamster ovary - CP cyclophosphamide - EMS ethylmethane sulfonate - ³H-dThd methyl-³H-thymidine - LDH lactate dehydrogenase - 3-MCA 3-methylcholanthrene - McN-5195 (±)-trans-3-(2-bromophenyl) octahydroindolizine - McN-5195-11 hydrochloride salt of McN-5195 - Na azide sodium azide - RCG relative clonal growth - RSG relative suspension growth - RTG relative total growth - SMF spontaneous mutation frequency - TEM triethylenemelamine - TFT trifluorothymidine     

Synthesis and antiproliferative activity of substituted benzopyranoisoindoles: a new class of cytotoxic compounds

A series of novel aminosubstituted benzopyranoisoindoles possessing structural analogy to an active nitracrine metabolite are reported. The compounds exhibited interesting cytotoxic activity against a panel of cell lines, which was maximized by the presence of both 1-dialkylaminoethyl and 3-nitro substituents.     

Synthesis and biological evaluation of novel carbazole-rhodanine conjugates as topoisomerase II inhibitors

In this study, a series of carbazole-rhodanine conjugates was synthesized and evaluated for their Topoisomerase II inhibition potency as well as cytotoxicity against a panel of four human cancer cell lines. Among these thirteen compounds, 3a, 3b, 3g, and 3h possessed Topoisomerase II inhibition potency at 20?μM. Mechanism study revealed that these compounds may function as Topo II catalytic inhibitors. It was found that the electron-withdrawing groups on the phenyl ring of compounds played an important role on enhancing both enzyme inhibition and cytotoxicity.     

Synthesis and biological evaluation of some novel thiazole substituted benzotriazole derivatives

A series of novel hybrid molecules 4a-y containing thiazole and benzotriazole templates were designed and synthesized. The structures of the synthesized compounds were elucidated by IR, (1)H NMR, (13)C NMR and mass spectral data. All the synthesized compounds were tested for their antimicrobial activity (zone of inhibition) against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. After that minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs) and minimum fungicidal concentrations (MFCs) of all the synthesized compounds were determined. The investigation of antimicrobial screening data revealed that most of the tested compounds showed moderate to good microbial inhibitions.     

Diheteroarylmethyl substituted titanocenes: A novel class of possible anti-cancer drugs

From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanocenes (5a-c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC₅₀) of 32 μM, 140 μM, and 240 μM, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.