HSP70 induction by bleomycin metal core analogs.

Induction of heat shock protein 70 (HSP70) is known to be effective against various diseases. We are interested in HSP70 induction capability of an antitumor antibiotic bleomycin which produces oxidative stress by iron chelate formation and oxygen activation in a cell. The HSP70 induction activity of bleomycin and its six metal core analogs was examined, and a compound HPH-1Trt of 10 µM was found to induce this protein in a pheochromocytoma cell line and some T cell and monocytic cell lines. Its mechanism is increase of HSP70 mRNA, but higher concentration of this compound showed toxicity. Two new derivatives were then synthesized, and one of them named DHPH-1Trt was shown to have less toxicity and higher HSP70 induction activity. This study would lead to a clue for new HSP70 inducer clinically used in near future.

Design, synthesis, molecular docking, anti-Proteus mirabilis and urease inhibition of new fluoroquinolone carboxylic acid derivatives.

New hydroxamic acid, hydrazide and amide derivatives of ciprofloxacin in addition to their analogues of levofloxacin were prepared and identified by different spectroscopic techniques. Some of the prepared compounds revealed good activity against the urease splitting bacteria, Proteus mirabilis. The urease inhibitory activity was investigated using indophenol method. Most of the tested compounds showed better activity than the reference acetohydroxamic acid (AHA). The ciprofloxacin hydrazide derivative 3a and levofloxacin hydroxamic acid 7 experienced the highest activity (IC50=1.22µM and 2.20µM, respectively). Molecular docking study revealed high spontaneous binding ability of the tested compounds to the active site of urease.

Design, synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors.

A group of novel chalcone derivatives comprising hydroxamic acid or 2-aminobenzamide group as zinc binding groups (ZBG) were synthesized. The structure of the prepared compounds was fully characterized by IR, NMR and elemental microanalyses. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds 4a and 4b exhibited significant anti-proliferative activity against the three cell lines compared to SAHA as reference drug and displayed promising profile as anti-tumor candidates. The results indicated that these chalcone derivatives could serve as a promising lead compounds for further optimization as antitumor agents.

Synthesis, cytotoxic activity, and tubulin polymerization inhibitory activity of new pyrrol-2(3H)-ones and pyridazin-3(2H)-ones.

A series of new pyrrol-2(3H)-ones 4a-f and pyridazin-3(2H)-ones 7a-f were synthesized and characterized using different spectroscopic tools. Some of the tested compounds revealed moderate activity against 60 cell lines. The E form of the pyrrolones 4 showed good cytotoxic activity than both the Z form and the corresponding open amide form. Furthermore, the in vitro cytotoxic activity against HepG2 and MCF-7 cell lines revealed that compounds (E)4b, 6f and 7f showed good cytotoxic activity against HepG2 with IC50 values of 11.47, 7.11 and 14.80µM, respectively. Compounds (E)4b, 6f, 7d and 7f showed a pronounced inhibitory effect against cellular localization of tubulin. Flow cytometric analysis indicated that HepG2 cells treated with (E)4b showed a predominated growth arrest at the S-phase compared to that of G2/M-phase. Molecular modeling study using MOE® program indicated that most of the target compounds showed good binding of ß-subunit of tubulin with the binding free energy (dG) values about -10kcal/mole.

New acyloxy nitroso compounds with improved water solubility and nitroxyl (HNO) release kinetics and inhibitors of platelet aggregation.

New acyloxy nitroso compounds, 4-nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trichloroacetate and 4-nitrosotetrahydro-2H-pyran-4-yl 2,2-dichloropropanoate were prepared. These compounds release HNO under neutral conditions with half-lives between 50 and 120min, identifying these HNO donors as kinetically intermediate to the much slower acetate derivative and the faster trifluoroacetic acid derivative. These compounds or HNO-derived from these compounds react with thiols, including glutathione, thiol-containing enzymes and heme-containing proteins in a similar fashion to other acyloxy nitroso compounds. HNO released from these acyloxy nitroso compounds inhibits activated platelet aggregation. These acyloxy nitroso compounds augment the range of release for this group of HNO donors and should be valuable tools in the further study of HNO biology.

Novel metal chelating molecules with anticancer activity. Striking effect of the imidazole substitution of the histidine-pyridine-histidine system.

Previously we have reported a metal chelating histidine-pyridine-histidine system possessing a trityl group on the histidine imidazole, namely HPH-2Trt, which induces apoptosis in human pancreatic adenocarcinoma AsPC-1 cells. Herein the influence of the imidazole substitution of HPH-2Trt was examined. Five related compounds, HPH-1Trt, HPH-2Bzl, HPH-1Bzl, HPH-2Me, and HPH-1Me were newly synthesized and screened for their activity against AsPC-1 and brain tumor cells U87 and U251. HPH-1Trt and HPH-2Trt were highly active among the tested HPH compounds. In vitro DNA cleavage assay showed both HPH-1Trt and HPH-2Trt completely disintegrate pUC19 DNA. The introduction of trityl group decisively potentiated the activity.

New nitric oxide donating 1,2,4-triazole/oxime hybrids: synthesis, investigation of anti-inflammatory, ulceroginic liability and antiproliferative activities.

A series of novel nitric oxide (NO) donating triazole/oxime hybrids was prepared and evaluated for their anti-inflammatory activity. Most of the tested compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared to indomethacin. Calculation of the ulcer indices and histopathological investigation indicated that the prepared NO-donating oximes exhibited less ulcerogenicity compared to their intermediate ketones and indomethacin. The NO-donating oxime 6i revealed significant activity against renal cancer A498 cell lines with 50.52 cell growth inhibition.

Synthesis, anti-inflammatory activity and ulcerogenic liability of novel nitric oxide donating/chalcone hybrids.

A group of novel nitric oxide (NO) donating chalcone derivatives was prepared by binding various amino chalcones with different NO donating moieties including; nitrate ester, oximes and furoxans. Most of the prepared compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared with indomethacin. The prepared compounds exhibited more protection than indomethacin in regard to gastric toxicity. Histopathological investigation confirmed the beneficial effects of the NO releasing compounds in reducing ulcer formation. The incorporation of the NO-donating group into the parent chalcone derivatives caused a moderate increase in the anti-inflammatory activity with a marked decrease in gastric ulcerations compared to their parent chalcone derivatives.

Anti-Proliferative and Pro-Apoptotic Activities of Synthesized 3,4,5 Tri-Methoxy Ciprofloxacin Chalcone Hybrid, through p53 Up-Regulation in HepG2 and MCF7 Cell Lines.

BACKGROUND: Cancer is a significant health problem around the world and one of the leading causes of human death. The need for novel, selective and non-toxic anti-cancer agents is still urging. AIM OF THE WORK: to investigate the anti-proliferative and pro-apoptotic effects of the synthesized ciprofloxacin 3,4,5 tri-methoxy chalcone hybrid (CCH) on the HepG2 hepatocellular carcinoma and MCF7 breast carcinoma cell lines. MATERIALS AND METHODS: HepG2 and MCF7cell lines were treated with CCH. Cell viability and cell cycle analysis were performed. Protein and mRNA expression levels of P53, COX-2 and TNF-α were analyzed by western blotting and RT-PCR respectively. RESULTS: CCH caused concentration and time-dependent reduction in the viability of human HepG2 and MCF7 cells, pre-G1 apoptosis and cell cycle arrest at G2/M stage, significantly higher P53 and TNF-α mRNA and protein expression levels but significantly lower COX2 mRNA and protein expression levels. CONCLUSION: CCH showed obvious anti-proliferative and apoptosis-inducing activities in both cell lines.

Synthesis, antitumor, antibacterial and urease inhibitory evaluation of new piperazinyl N-4 carbamoyl functionalized ciprofloxacin derivatives.

BACKGROUND: Quinolones are well known antibacterial chemotherapeutics. Furthermore, they were reported for other activities such as anticancer and urease inhibitory potential. Modification at C7 of quinolones can direct these compounds preferentially toward target molecules. METHODS: Different derivatives of ciprofloxacin by functionalization at the piperazinyl N-4 position with arylidenehydrazinecarbonyl and saturated heterocyclic-carbonyl moieties have been synthesized and characterized using different spectral and analytical techniques. The synthesized compounds were evaluated for anticancer, antibacterial, and urease inhibitory activities. RESULTS: Among the synthesized compounds derivatives 3f and 3g experienced a potent antiproliferative activity against the breast cancer BT-549 cell line, recording growth percentages of 28.68% and 6.18%, respectively. Additionally, compound 3g revealed a remarkable antitumor potential toward the colon cancer HCT-116 cells (growth percentage 14.76%). Activity of compounds 3f and 3g against BT-549 cells was comparable to doxorubicin (IC50 = 1.84, 9.83, and 1.29 µM, respectively). Test compounds were less active than their parent drug, ciprofloxacin toward Klebsiella pneumoniae and Proteus mirabilis. However, derivative 4a showed activity better than chloramphenicol against Klebsiella pneumoniae (MIC = 100.64 and 217.08 µM, respectively). Meanwhile, many of the synthesized compounds revealed a urease inhibitory activity greater than their parent. Compound 3i was the most potent urease inhibitor with IC50 of 58.92 µM, greater than ciprofloxacin and standard inhibitor, thiourea (IC50 = 94.32 and 78.89 µM, respectively). CONCLUSION: This study provided promising derivatives as lead compounds for development of anticancer agents against breast and colon cancers, and others for optimization of urease inhibitors.

N-malonyl-1,2-dihydroisoquinoline as a novel carrier for specific delivery of drugs to the brain.

N-Malonyl-1,2-dihydroisoquinoline derivatives were synthesized and investigated as a novel carrier system for site-specific and sustained delivery of drugs to the brain. Such carriers are expected to be stable against air oxidation due to the presence of the carbonyl group close to nitrogen of the dihydroisoquinoline. Reduction of the prepared isoquinolinium quaternary derivatives with sodium dithionite afforded a novel group of N-malonyl-1,2-dihydroisoquinoline chemical delivery systems (CDS). The synthesized N-malonyl-1,2-dihydroisoquinoline chemical delivery systems were subjected to various chemical and biological investigations to evaluate their ability to cross the blood-brain barrier (BBB), and to be oxidized biologically into their corresponding quaternary derivatives. The in-vitro oxidation studies showed that the designed N-malonyl-1,2-dihydroisoquinoline chemical delivery system could be oxidized into its corresponding quaternary derivatives at an adequate rate. The in-vivo distribution studies showed that these N-malonyl-1,2-dihydroisoquinoline chemical delivery systems were able to cross the blood-brain barrier at detectable concentrations.

Thieno[2,3-d]pyrimidines in the synthesis of antitumor and antioxidant agents.

Dimethyl acetylenedicarboxylate, ethyl propiolate, and E-dibenzoylethylene react with thienopyrimidines (cyclo-pentyl, -hexyl, and -heptyl) derivatives to form thiazolo[3,2-a]thieno-[2,3-d]pyrimidin-2-ylidene) acetates, thieno[2,3-d]pyrimidin-2-ylthioacrylates, and thieno[2',3':4,5]pyrimido[2,1-b][1,3]thiazin-6-ones, respectively. Reactions proceed via cyclization and thio-addition processes. Some derivatives of thienopyrimidines showed high inhibition of Hep-G2 cell growth compared with the growth of untreated control cells. However, the fused heptyl of thienopyrimidothiazines indicates a promising specific antitumor agent against Hep-G2 cells with IC(50 )< 20 microM.

Design, synthesis, antibacterial activity and physicochemical parameters of novel N-4-piperazinyl derivatives of norfloxacin.

We report herein the synthesis of some N-Mannich bases in addition to different N-4 substituents of norfloxacin. The antibacterial activities of the newly synthesized compounds were evaluated and correlated with their physicochemical properties. Results revealed that some of the tested compounds exhibited better inhibitory activities than the reference antibiotic norfloxacin against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia and Staphylococcus aureus strains. Correlation results showed that there is no single physicochemical parameter that can determine the effect of N-4 piperazinyl group on the activity of these fluoroquinolones, where lipophilicity, molecular mass and electronic factors may influence the activity.

1-Malonyl-1,4-dihydropyridine as a novel carrier for specific delivery of drugs to the brain.

A group of 1-malonyl-1,4-dihydropyridine derivatives were synthesized as novel carrier systems for site-specific and sustained drug delivery to the brain. Such carriers are expected to be stable against air oxidation due to the presence of the carbonyl group close to nitrogen of the dihydropyridine. These carrier systems were attached to a group of different aldehydes to afford novel quaternary pyridinium derivatives 9a-e, 11a-d, 13 and 18a-b. Reduction of the prepared quaternary pyridinium derivatives with sodium dithionite afforded a novel group of 1-malonyl-1,4-dihydropyridine chemical delivery systems (CDSs) 10a-e, 12a-d, 14 and 19a-b. The synthesized 1-malonyl-1,4-dihydropyridine CDSs were subjected to various chemical and biological investigations to evaluate their ability to cross the blood-brain barrier, and to be oxidized biologically into their corresponding quaternary derivatives. The in vitro oxidation studies showed that most of the 1-malonyl-1,4-dihydropyridine CDSs could be oxidized into their corresponding quaternary derivatives at an adequate rate. The in vivo studies showed that compounds 10c and 14 were able to cross the blood-brain barrier at detectable concentrations. Moreover, the pyridinium quaternary intermediates 9a, 9c, 13, 18a and their corresponding dihydro derivatives 10a, 10c, 14 and 19a were screened for their antidepressant activity using tail suspension behavioral despair test compared to imipramine as a reference at a dose level of 10mg/kg. The results indicated that compounds 13, 14 and 19a induced remarkable antidepressant activity comparable to imipramine. Compounds 10a, 10c and 18a exhibited good antidepressant activity, their activities nearly equal to 92.8%, 86.7% and 90.20% of the activity of imipramine, respectively. The other derivatives 9a and 9c exhibited moderate antidepressant activity compared with imipramine.

Design, synthesis and biological investigation of certain pyrazole-3-carboxylic acid derivatives as novel carriers for nitric oxide.

Some novel pyrazole-NO hybrid molecules 5a-e, 6, 8 and 10 were prepared through binding of the pyrazole-3-carboxylic acid derivatives with nitric oxide donor moiety like oxime or nitrate ester. The prepared compounds were evaluated for nitric oxide release, antibacterial and anti-inflammatory activities. The organic nitrate 10 exhibited the highest percentage of NO release using Griess diazotization method. Some of the prepared compounds exhibited remarkable antibacterial activity against Escherichia coli C-600, Pseudomonas aeruginosa, Bacillus subitilis and Staphylococcus aureus NCTC 6571 compared to ciprofloxacin. Most of the tested compounds showed significant anti-inflammatory activity compared to indomethacine using carrageenan induced paw edema method. In general, structural modification of compound 2 either to nitrate ester or oxime hybrids showed better anti-inflammatory with less ulcerogenic liability than their corresponding starting intermediates.

Current Trends and Future Directions of Fluoroquinolones.

Fluoroquinolones represent an interesting synthetic class of antimicrobial agents with broad spectrum and potent activity. Since the discovery of nalidixic acid, the prototype of quinolones, several structural modifications to the quinolone nucleus have been carried out for improvement of potency, spectrum of activity, and to understand their structure activity relationship (SAR). The C-7 substituent was reported to have a major impact on the activity. Accordingly, Substitution at C-7 or its N-4-piperazinyl moiety was found to affect potency, bioavailability, and physicochemical properties. Also, it can increase the affinity towards mammalian topoisomerases that may shift quinolones from antibacterial to anticancer candidates. Moreover, the presence of DNA topoisomerases in both eukaryotic and prokaryotic cells makes them excellent targets for chemotherapeutic intervention in antibacterial and anticancer therapies. Based on this concept, several fluoroquionolones derivatives have been synthesized and biologically evaluated as antibacterial, antituberculosis, antiproliferative, antiviral and antifungal agents. This review is an attempt to focus on the therapeutic prospects of fluoroquinolones with an updated account on their atypical applications such as antitubercular and anticancer activities.

NO-donors, part 9 : diazeniumdiolates inhibit human platelet aggregation and induce a transient vasodilatation of porcine pulmonary arteries in accordance with the NO-releasing rates.

Diazeniumdiolates (NONOates), among them a ciprofloxacin-diazeniumdiolate hybrid compound, were synthesized and the pH-, temperature- and structure-dependent liberation of nitric oxide (NO) was monitored by laser magnetic resonance spectroscopy (LMRS). The compounds induced a transient and reversible relaxation (EC(50) 8.3-150 nM) of pulmonary arteries independently from intact endothelium by stimulation of guanylyl cyclase (sGC). Increase in vascular cGMP was observed and blocking sGC with ODQ, an inhibitor of the NO-sensitive guanylyl cyclase, induced a rightward shift of the concentration-response curves. Repeated exposure did not show homologous desensitization. ADP-induced platelet aggregation (IC(50) = 0.15-3 microM, IC(50) for SNP: 2 microM) and collagen-induced aggregation were potently inhibited. Preincubation with ODQ also diminished these inhibitory effects.

Novel 1-[4-(Aminosulfonyl)phenyl]-1H-1,2,4-triazole derivatives with remarkable selective COX-2 inhibition: design, synthesis, molecular docking, anti-inflammatory and ulcerogenicity studies.

A novel series of 1,2,4-triazole derivatives were synthesized and confirmed with different spectroscopic techniques. The prepared compounds exhibited remarkable anti-inflammatory activity comparable to that of indomethacin and celecoxib after 3 h. The tested compounds exhibited very low incidence of gastric ulceration compared to indomethacin. Most of the newly developed compounds showed excellent selectivity towards human COX-2 with selectivity indices (COX-1 IC50/COX-2 IC50) ranged from 62.5 to 2127. Docking studies results revealed that the highly selective tested compounds 6h and 6j showed lower CDOCKER energies, which means that they require less energy for proper interaction with the enzyme. The additional H-bonds with the oxygen of the amide and/or H of NH of the amide with the amino acid residues may be responsible for the higher binding affinity of this group of compounds towards COX-2.

1,2,4-Triazole/oxime hybrids as new strategy for nitric oxide donors: Synthesis, anti-inflammatory, ulceroginicity and antiproliferative activities.

A series of novel nitric oxide (NO) donating triazole/oxime hybrids was prepared and evaluated for their anti-inflammatory activity and antiproliferative activity. Most of the tested compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared to indomethacin. Calculation of the ulcer indices and histopathological investigation indicated that the prepared NO-donating oximes exhibited less ulcerogenicity compared to their ketone intermediates and indomethacin. The NO-donating oximes 7i and 7k achieved remarkable cell growth inhibition activity against most of the tested cell lines. Compound 7k was found to be with high selectivity against CNS subpanel with selectivity ratio of 11.99 at GI50 level.

Novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids: synthesis, physicochemical properties, anticancer and topoisomerase I and II inhibitory activity.

A group of novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids was prepared. One-dose anticancer test results indicated that compounds 3a and 3g exhibited the highest ability to inhibit the proliferation of different cancer cell lines. Compound 3a exhibited a broad-spectrum of anti-tumor activity without pronounced selectivity while compound 3g revealed high selectivity toward the leukemia subpanel with selectivity ratio of 6.71 at GI50 level. Moreover, compounds 3e and 3j have shown remarkable topo II inhibitory activity compared to etoposide at 100 µM and 20 µM concentrations. Compounds 3e and 3j exhibited comparably potent topo I inhibitory activity at 20 µM concentration compared to camptothecin. Compounds 3e and 3j exhibited strong topo II inhibitory activities compared to topo I at 20 µM concentration. Studying of the solubility and partition coefficient revealed higher lipophilicity of the hybrids 3a-j compared to the parent ciprofloxacin.