Synthesis and crystal structures of (E)-N'-(4-chloro-3-nitro-benzyl-idene)acetohydrazide and (E)-2-(4-chloro-benzyl-idene)-1-(quinolin-8-yl)hydrazine.

The syntheses of two benzyl-idenehydrazine derivatives, namely, (E)-N'-(4-chloro-3-nitro-benzyl-idene)acetohydrazide, C9H8ClN3O3, and (E)-2-(4-chloro-benzyl-idene)-1-(quinolin-8-yl)hydrazine, C16H12ClN3, are reported. The mol-ecules have been characterized using IR, 1H NMR, 13C NMR and mass spectro-scopic and elemental analysis techniques, and their structures have been determined by single-crystal X-ray diffraction.

Tail-approach based design, synthesis, and cytotoxic evaluation of novel disubstituted and trisubstituted 1,3-thiazole benzenesulfonamide derivatives with suggested carbonic anhydrase IX inhibition mechanism.

A novel series of 2,4,5- and 2,3,4-trisubstituted thiazole hybrids with 1,3,4-thiadiazolylbenzenesulfonamide was designed following the tail approach as possible hCAIX inhibitors. The key intermediate 1 was condensed with thiosemicarbazide 2a to give 1,3,4-thiadiazolylthiosemicarbazone 3, which upon hetero-cyclization with substituted α-haloketones and esters afforded 2,4,5-trisubstituted thiazole-1,3,4-thiadiazole conjugates 4-8. Furthermore, the trisubstituted thiazole-1,3,4-thiadiazole hybrids 12a-d were synthesized via the regioselective cyclization of 4-substituted-1,3,4-thiadiazolylthiosemicarbazones with phenacyl bromide. The cyclized 2,4-disubstituted thiazole 4 enhanced cytotoxicity by nine, four and two times against HepG-2, Caco2, and MCF-7, respectively. Moreover, the simple methyl substitution on the thiosemicarbazone terminus 9a improved the parent derivative 3 cytotoxicity by nine, fourteen, and six times against HepG-2, Caco2, and MCF-7, respectively. This astonishing cytotoxicity was elaborated with hCAIX molecular docking simulation of 4, 9a, and 12d demonstrating binding to zinc and its catalytic His94. Furthermore, molecular dynamic simulation 9a revealed stable hydrogen bonding with hCAIX with interaction energy of -61.07 kcal mol-1 and ΔGbinding MM-PBSA of -9.6 kcal mol-1.

Design, synthesis and cytotoxic evaluation of novel bis-thiazole derivatives as preferential Pim1 kinase inhibitors with in vivo and in silico study.

Bis-thiazole derivatives were synthesised conforming to the Pim1 pharmacophore model following Hantzsch condensation. Pim1 has a major role in regulating the G1/S phase which upon inhibition the cell cycle stops at its early stages. Derivatives 3b and 8b showed the best Pim1 IC50 0.32 and 0.24 µM, respectively relative to staurosporine IC50 0.36 µM. Further confirmation of 3b and 8b Pim1 inhibition was implemented by hindering the T47D cell cycle at G0/G1 and S phases where 3b showed 66.5% cells accumulation at G0/G1 phase while 8b demonstrated 26.5% cells accumulation at the S phase compared to 53.9% and 14.9% of a control group for both phases, respectively. Additional in vivo cytotoxic evaluation of 3b and 8b revealed strong antitumor activity with up-regulation of caspase-3 and down-regulation of VEGF and TNF α immune expression with concomitant elevation of malondialdehyde levels in case of 8b.

Novel 6-Aminoquinazolinone Derivatives as Potential Cross GT1-4 HCV NS5B Inhibitors.

Chronic hepatitis C virus (HCV) infections are a worldwide medical problem responsible for diverse types of liver diseases. The NS5B polymerase enzyme has become a very interesting target for the development of anti-HCV drugs owing to its fundamental role in viral replication. Here we report the synthesis of a novel series of 1-substituted phenyl-4(1H)-quinazolinone and 2-methyl-1-substituted phenyl-4(1H)-quinazolinone derivatives and evaluate their activity against HCV in HCV subgenomic replicon assays. The biological data revealed that compound 11a showed the highest activity against HCV GT1b at a micromolar concentration (EC50 = 0.984 µM) followed by compound 11b (EC50 = 1.38 µM). Both compounds 11a and 11b had high selectivity indices (SI = CC50/EC50), 160.71 and 71.75, respectively, which make them very interesting candidates for further development of more potent and selective anti-HCV agents.

Design, synthesis, and molecular modeling of coumarin derivatives as MDM2 inhibitors targeting breast cancer.

The coumarin ring was used as a central scaffold that was substituted with a variety of bioactive functional groups, for designing and synthesizing novel MDM2 inhibitors targeting breast cancer. The synthesized derivatives, 3c, 3d, 3g, 7b, 7c and 8 with IC50s ranging from 9.4 to 9.9 µM were evaluated for their safety on MCF10a normal breast cell line. The compounds showed selectivity indices of 2.15, 3.85, 2.75, 1.38, 3.72 and 5.20 respectively. 7c was selected for further investigation, the compound was capable of down-regulating MDM2 and the anti-apoptosis proteins Bcl-2 and Bcl-xL, up-regulating the level of p53 and the pro-apoptosis protein BAX, causing cell cycle arrest at G2/M phase and activating Caspase-9 to induce apoptosis. Molecular docking study revealed the capability of derivative 7c to interact with the key amino acids in p53 binding pocket of MDM2 protein. Moreover, the physicochemical properties of compound 7c were studied in silico.

Bactericidal activity of a substituted thiazole against multidrug-resistant Eggerthia catenaformis isolated from patients with dental abscess.

Human infections caused by the anaerobic bacterium Eggerthia catenaformis are rare. However, a growing number of case reports have presented the bacterium as the causative agent in many serious complications. This study provides data on the isolation and antibiotic susceptibility profiles of E. catenaformis from dental abscess. Identification of isolates was performed using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). We also investigated the antibacterial activity of 5-acetyl-4-methyl-2-(3-pyridyl) thiazole (AMPT) on E. catenaformis isolates. Minimum inhibitory concentrations (MICs) were determined by an agar dilution method and bactericidal activity was evaluated by a time-kill assay. Moreover, the mechanism of action of AMPT was also explored by cell membrane disruption assay and scanning electron microscopy (SEM). MALDI-TOF MS results revealed unambiguous identification of all isolates with score values between 2.120 and 2.501. Isolates NY4 and NY9 (20% of isolates) were found resistant to multiple antibiotics judged by MIC values. As multidrug-resistant strains of E. catenaformis were not reported to date, we then confirmed the identity of NY4 and NY9 based on 16S rRNA gene sequence. Favorably, all isolates were susceptible to AMPT with an MIC range of 0.25-1 mg/L. Time-kill kinetics of AMPT indicated that it exhibited potent bactericidal activity against the multidrug-resistant isolates NY4 and NY9. Furthermore, this study also hypothesizes that AMPT exerts its antibacterial effect through damaging the cell membrane and thereby induce the release of intracellular components. AMPT could therefore be considered as a therapeutic option for infections caused by multidrug-resistant bacteria.

Biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs as novel VEGFR2 inhibitors; Design, synthesis and anti-angiogenic activity.

Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as a vital tool for cancer treatment. In this study, a new series of biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs (3a-l) was designed and synthesized as novel VEGFR2 inhibitors. The biochemical profiles of the target compounds were investigated using viability of human umbilical vascular endothelial cells (HUVECs), migration assay and Western blot using sorafenib as reference antiangiogenic drug. Most of the tested compounds exhibited significant antiproliferative activity against HUVECs, where compounds 3a, 3e, 3g, 3h and 3l exhibited better antiproliferative activity than sorafenib. All compounds significantly inhibited VEGF stimulated migration of HUVECs at 10 µM dose with (3a, 3e, 3g, 3h and 3l) showing better or comparable inhibitory activities to that of sorafenib. Moreover, Western blotting analysis confirmed antiangiogenic effect of those compounds with significant reduction in the level of VEGFR-2 compared to sorafenib. Finally, cytotoxicity screening of these derivatives against four cancer cells and RPE1 as normal cell line was performed. The mechanistic effectiveness in cell cycle progression and apoptotic induction were evaluated for the promising compound 3e due to its remarkable cytotoxic activity against tested cancer cell lines and significant VEGFR-2 inhibition. Flow cytometric analysis showed that compound 3e induced cell growth arrest at G2/M phase and stimulated the apoptotic death of HepG2 cells.

Antibacterial and anti-quorum sensing activities of a substituted thiazole derivative against methicillin-resistant Staphylococcus aureus and other multidrug-resistant bacteria.

Management of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) is still challenging. We herein report the antibacterial and anti-quorum sensing (anti-QS) activities of 5-acetyl-4-methyl-2-(3-pyridyl) thiazole (AMPT) against MRSA and other multidrug-resistant bacteria. Minimum inhibitory concentrations (MICs) were determined by agar dilution method and bactericidal activity was assessed by a time-kill assay. The anti-QS activity was evaluated using Chromobacterium violaceum. The effect of AMPT on virulence factors production by MRSA and biofilm formation by MRSA, C. violaceum and Pseudomonas aeruginosa was also assessed. AMPT was superior to vancomycin and teichoplanin against MRSA isolates. MIC50/90 values of AMPT (2/4 mg/L) were 2-4 folds lower than the values for vancomycin (4/16 mg/L) and 2-fold lower than the values for teichoplanin (4/8 mg/L). Results of time-kill assay against two multidrug-resistant MRSA isolates revealed bactericidal effect of AMPT after 4 h of treatment, with no bacterial cells detected after 24 h. Remarkably, AMPT exhibited anti-QS activity against both C. violaceum and MRSA at subinhibitory concentrations. Moreover, AMPT reduced haemolysin and protease production by MRSA and inhibited biofilm formation by MRSA, C. violaceum and P. aeruginosa but had no dispersion effect on preformed ones. Furthermore, molecular docking analysis revealed promising interactions between AMPT and AgrA as well as SarA in S. aureus confirming the antivirulence and antibiofilm activities. Favourably, no significant cytotoxicity of AMPT was observed on murine macrophage cell line. Taken altogether, these results suggest that AMPT could be considered an interesting lead compound in the search for treatment of MRSA infections.

New acrylamide-sulfisoxazole conjugates as dihydropteroate synthase inhibitors.

New functionalized acrylamide derivatives bearing sulfisoxazole moiety were designed to target bacterial dihydropteroate synthase (DHPS). The in vitro antimicrobial activities of these compounds were assessed. The E-configuration of compound 5b was proved by single crystal X-ray analysis. Compounds 5g and 5h displayed double the activity of ampicillin against B. subtilis. Also, 5h was two times more active than gentamycin against E. coli. Interestingly, compounds 5f-g, 7c, 8a, 8c exhibited two folds the potency of amphotericin B against S. racemosum while 5h displayed three folds the activity of amphotericin B against S. racemosum. Most of the synthesized compounds showed superior activities to the parent sulfisoxazole and were non-toxic to normal cells. DHPS is confirmed to be a putative target for our compounds via antagonizing their antibacterial activity by the folate precursor (p-aminobenzoic acid) and product (methionine) on E. coli ATCC 25922. Docking experiments against DHPS rationalized the observed antibacterial activity. Additionally, compound 5g was evaluated as a selective targeting vector for 99mTc that showed a remarkable uptake and targeting ability towards the infection site that was induced in mice.

Novel LC-MS/MS method for analysis of metformin and canagliflozin in human plasma: application to a pharmacokinetic study.

Highly sensitive and selective liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous estimation of the recently approved oral hypoglycemic mixture; metformin (MET) and canagliflozin (CFZ) in human plasma using propranolol HCl (PPL) and tadalafil (TDF) as internal standards (IS), respectively. Analytes were extracted using protein precipitation induced by acetonitrile then liquid-liquid extraction was performed using ethyl acetate. Reversed phase HPLC was carried out using C18 analytical column (50 mm × 4.6 mm i.d., 5 µm) with a simple isocratic mobile phase composed of 0.1% formic acid and acetonitrile (60:40, v/v). Detection was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique, operating in multiple reaction monitoring (MRM), with the transitions of m/z 130.2 → 60.1, m/z 462.3 → 191.0, m/z 260.2 → 183.0 and m/z 390.2 → 268.2 for MET, CFZ, PPL and TDF, respectively, in the positive ion mode. The analysis was carried out within 5 min over a linear concentration range of 50-5000 ng/mL for MET and 10-1000 ng/mL for CFZ. The method was validated in accordance with the FDA guidelines for bioanalytical method. All obtained recoveries were higher than 90.0% while the accuracy was in the range of 88.14-113.05% and the relative standard deviation was below 10.0% for all investigated drugs by the proposed method. The achieved promising results has allowed for the successful application of the developed LC-MS/MS method to a pharmacokinetic study of the target drugs after their oral administration to Egyptian healthy volunteers. The pharmacokinetic study was accomplished after the agreement of the ethics committee.

Design, Synthesis and Biological Evaluation of Spiro Cyclohexane-1,2- Quinazoline Derivatives as Potent Dipeptidyl Peptidase IV Inhibitors.

OBJECTIVE: Inhibition of dipeptidyl peptidase IV (DPP-4) is currently one of the most valuable and potential chemotherapeutic regimes for the medication of Type 2 Diabetes Mellitus (T2DM). METHOD: Based on linagliptin, this study discusses the design, synthesis and biological evaluation of spiro cyclohexane-1,2'-quinazoline scaffold hybridized with various heterocyclic ring systems through different atomic spacers as a highly potent DPP-4 inhibitors. DPP-4 enzyme assay represented that most of the target compounds are 102-103 folds more active than the reference drug linagliptin (IC50: 0.0005-0.0089 nM vs 0.77 nM; respectively). Moreover, in vivo oral hypoglycemic activity assay revealed that most of the tested candidates were more potent than the reference drug, sitagliptin, producing rapid onset with long duration of activity that extends to 24 h. Interestingly, the derivatives 11, 16, 18a and 23 showed evidence of mild cytochrome P450 3A4 (CYP3A4) inhibition (IC50; > 210 µM) and their acute toxicity (LD50) was more than 1.9 gm/kg. Molecular simulation study of the new quinazoline derivatives explained the obtained biological results. CONCLUSION: Finally, we conclude that our target compounds could be highly beneficial for diabetic patients in the clinic.

Novel hydrazide-hydrazone and amide substituted coumarin derivatives: Synthesis, cytotoxicity screening, microarray, radiolabeling and in vivo pharmacokinetic studies.

The current work presents the synthesis and biological evaluation of new series of coumarin hydrazide-hydrazone derivatives that showed in vitro broad spectrum antitumor activities against resistant pancreatic carcinoma (Panc-1), hepatocellular carcinoma (HepG2) and leukemia (CCRF) cell lines using doxorubicin as reference standard. Bromocoumarin hydrazide-hydrazone derivative (BCHHD) 11b showed excellent anticancer activity against all tested cancer cell lines. Enzyme assays showed that BCHHD 11b induced apoptosis due to activation of caspases 3/7. Moreover, 11b inhibited GST and CYP3A4 in a dose dependent manner and the induced cell death could be attributed to metabolic inhibition. Moreover, 11b microarray analysis showed significant up- and down-regulation of many genes in the treated cells related to apoptosis, cell cycle, tumor growth and suppressor genes. All of the above presents BCHHD 11b as a potent anticancer agent able to overcome drug resistance. In addition, compound 11b was able to serve as a chemical carrier for 99mTc and the in vivo biodistribution study of 99mTc-11b complex revealed a remarkable targeting ability of 99mTc into solid tumor showing that 99mTc-11b might be used as a promising radiopharmaceutical imaging agent for cancer.

Synthesis, antitumor evaluation and microarray study of some new pyrazolo[3,4-d][1,2,3]triazine derivatives.

Design and synthesis of new anticancer scaffolds; pyrazolo[3,4-d][1,2,3]triazine derivatives, is a promising solution to overcome drug resistance problem. A series of (E)-2-cyano-N-(aryl)-3-methylthio-3-(substituted-amino)acrylamides 3a-e was synthesized and transformed to the 3-aminopyrazole derivatives 4a-e which were then transformed to the target pyrazolotriazinones 6a-e. All compounds were evaluated for their anticancer activity against three different cancer cell lines namely Huh-7, Panc-1 and CCRF. Compounds 3a, 3c, 6a and 6c showed excellent anticancer activity against Huh-7 cell line (IC50: 4.93-8.84 µM vs doxorubicin 5.43 µM). Similarly, compounds 6a and 6d showed excellent activities against Panc-1 cells (IC50: 9.91 µM and 4.93 µM vs doxorubicin 6.90 µM). Caspase-Glo 3/7 assay was done and the results revealed that the pro-apoptotic activity of the target compounds could be due to the stimulation of caspases 3/7. Microarray experiment for Huh-7 cells treated with 6c was performed to search for other molecular changes. SLC26A3, UGT1A1, UGT2B15, UGT2B7, DNASE1, MUCDH1 and UGT2B17 were among the up-regulated genes, while, GIP3, TAGL, THBS1, IFI27, FSCN1 and SOCS2 were among the most extensively down-regulated genes. These genes belong to apoptosis, metabolism, cell cycle, tumor growth and suppressor genes. Finally, pyrazolo[3,4-d][1,2,3]triazine derivatives could be potent anticancer drugs in the future.

Generation of a cell-permeable cycloheptapeptidyl inhibitor against the peptidyl-prolyl isomerase Pin1.

Cyclic peptides are capable of binding and modulating challenging drug targets including protein-protein interactions. However, their lack of membrane permeability prevents their application against intracellular targets. In this study, we show that it is possible to design a cell-permeable and biologically active cycloheptapeptide inhibitor against the intracellular enzyme peptidyl-prolyl isomerase Pin1 by integrating cell-penetrating and target-binding sequences.

Design, synthesis, antimicrobial evaluation and molecular docking studies of some new 2,3-dihydrothiazoles and 4-thiazolidinones containing sulfisoxazole.

Microbial resistance to the available drugs poses a serious threat in modern medicine. We report the design, synthesis and in vitro antimicrobial evaluation of new functionalized 2,3-dihydrothiazoles and 4-thiazolidinones tagged with sulfisoxazole moiety. Compound 8d was most active against Bacillis subtilis (MIC, 0.007 µg/mL). Moreover, compounds 7c-d and 8c displayed significant activities against B. subtilis and Streptococcus pneumoniae (MIC, 0.03-0.06 µg/mL and 0.06-0.12 µg/mL versus ampicillin 0.24 µg/mL and 0.12 µg/mL; respectively). Compounds 7a and 7c-d were highly potent against Escherichia coli (MIC, 0.49-0.98 µg/mL versus gentamycin 1.95 µg/mL). On the other hand, compounds 7e and 9c were fourfolds more active than amphotericin B against Syncephalastrum racemosum. Molecular docking studies showed that the synthesized compounds could act as inhibitors for the dihydropteroate synthase enzyme (DHPS). This study is a platform for the future design of more potent antimicrobial agents.

The effect of laser photobiomodulation diode laser (Ga-As) 100 mW on temporomandibular joint anterior disc displacement: preliminary study

Background: Superpulsed low-level laser therapy (LLLT) seems to be a good choice as a non-invasive treatment for temporomandibular joint (TMJ) disorders and pain. Objectives. The purpose of this study is to clinically evaluate the effectiveness of splint for treatment of anterior disc displacement with reduction of the TMJ with or without LLLT. Material and methods. This was a prospective experimental study that included 20 female patients with anterior disc displacement with reduction of the TMJ. Patients were randomly assigned into two groups of 10 each. Patients of Group I were subjected to LLLT during four weeks, together with stabilization appliance splint for treatment of anterior disc displacement with reduction of the TMJ. Patients were evaluated before treatment, after six sessions of laser therapy, after 12 sessions of laser therapy, and 1 month after the last session. Patients of Group II were subjected to only stabilization appliance splint. Results. Follow up of maximum mouth opening in mm before and after treatment in Group I showed statistically significant difference with p value<0.001. In concordance, Follow up of visual analog scale (VAS) for pain before and after treatment in Group I showed statistically significant difference with p value<0.001. Comparisons between both groups before and after treatment showed significant improvements in the maximum mouth opening in mm and VAS for pain in Group I. Conclusions. Splint and LLLT in patients with anterior disc displacement with reduction of the TMJ are more effective than splint alone. The application of LLLT is proved to be safe and improves the results of the splint

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Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran-pyrazole derivatives as anticancer agents.

This study deals with design and synthesis of novel benzofuran-pyrazole hybrids as anticancer agents. Eight compounds were chosen by National Cancer Institute (NCI), USA to evaluate their in vitro antiproliferative activity at 10(-5)M in full NCI 60 cell panel. The preliminary screening of the tested compounds showed promising broad-spectrum anticancer activity. Compound 4c was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Leukemia CCRF-CEM, MOLT-4, Lung Cancer HOP-92, Colon Cancer HCC-2998, CNS Cancer SNB-75, Melanoma SK-MEL-2, Ovarian Cancer IGROV1, Renal Cancer 786-0, RXF 393, Breast Cancer HS 578T and T-47D (GI50: 1.00-2.71µM). Moreover, enzyme assays were carried out to investigate the possible antiproliferative mechanism of action of compound 4c. The results revealed that compound 4c has good c-Src inhibitory activity at 10µM. In addition, molecular docking studies showed that 4c could bind to the ATP Src pocket sites. Fulfilling the Lipinskiís rule of five in addition to its ADME profile and the biological results, all strongly suggest that 4c is a promising Src kinase inhibitor.

Design, synthesis, antimicrobial evaluation and molecular docking studies of some new thiophene, pyrazole and pyridone derivatives bearing sulfisoxazole moiety.

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. In this context, new functionalized thiophene, acrylamide, arylhydrazone, pyrazole and pyridone derivatives bearing sulfisoxazole moiety were designed, synthesized and evaluated for their in vitro antibacterial and antifungal activities. Among the synthesized compounds, thiophene 4d and 6-thioglucosylpyridone 17 displayed significant antibacterial activities against Escherichia coli (MIC, 0.007 µg/mL vs gentamycin 1.95 µg/mL) and Bacillis subtilis (MIC, 0.007 µg/mL vs ampicillin 0.24 µg/mL), respectively. Whereas, the pyrazole 6 showed the highest antifungal activity against Aspergillus fumigates (MIC, 0.03 µg/mL vs amphotericin B 0.12 µg/mL). In general, most of the synthesized compounds exhibited better antimicrobial activities than sulfisoxazole; this might be attributed to the synergistic effect of the sulfonamide and attached heterocyclic moieties as well as the increased lipophilic characters of the synthesized compounds. Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of microbial DHPS enzyme. The results provide important information for the future design of more potent antimicrobial agents.

Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives.

Drug resistance is a major impediment for cancer treatment, to overcome it we designed and synthesized sixteen coumarins bearing hydrazide-hydrazone moiety and evaluated them against human drug-resistant pancreatic carcinoma (Panc-1) cells and drug-sensitive (hepatic carcinoma; Hep-G2 and leukemia; CCRF) cell lines in vitro. The 6-brominated coumarin hydrazide-hydrazone derivatives (BCHHD) 7c, 8c and 10c were more potent than doxorubicin (DOX) against resistant Panc-1 cells. BCHHD 7c showed significant cytotoxicity against all tested cells (IC50: 3.60-6.50 µM) on comparison with all other coumarin hydrazide-hydrazone derivatives (CHHD), whereas BCHHD's 8c and 10c showed significant antiproliferative activity only against resistant Panc-1 cells with IC50 of 2.02 µM and 2.15 µM, respectively. All the investigated BCHHD's were able to activate caspases 3/7 and they could induce apoptosis in resistant Panc-1 cells. Microarray analysis showed that BCHHD 7c induced the expression of apoptotic- and cell cycle arrest (G2/M)- genes in resistant Panc-1 cells. Moreover, BCHHD 7c induced the up-regulation of CDKN1A, DDIT4, GDF-15 and down-regulation of CDC2, CDC20, CDK2 genes. Based on our results, we conclude that 7c could be a potent anticancer drug to overcome drug resistance in cancer and it could be highly beneficial for patients in the clinic.

Properties of oligonucleotide with phenyl-substituted carbocyclic nucleoside analogs for the formation of duplex and triplex DNA.

(1S,3S,4R)-1-Phenyl-1-thymidyl-3-hydroxy-4-hydroxymethylcyclopentane (10) and their analogs were synthesized, incorporated into the oligodeoxynucleotides, and their properties were evaluated for the formation of duplex and triplex DNA. The known chiral cyclopentanone derivative was converted into the corresponding ketimine sulfonamide derivative, which was subjected to a stereoselective PhLi addition. The formed sulfonamide was hydrolyzed to afford the primary amino group, on which the thymine moiety was built. The benzyl protecting groups were removed to form the nucleoside analog having a phenyl group and the thymine unit at the 1' position of a carbocyclic skeleton (10). In the estimation of the oligodeoxynucleotides incorporating 10 for duplex and triplex formation, the carbocyclic nucleoside analog 10 did not show the stabilizing effect for duplex formation; on the other hand, it stabilized the triplex. Therefore, the skeleton of the phenyl-substituted carbocyclic nucleoside analog 10 may be a platform for the formation of stable triplex DNA.