An-Najah Blogs :: http://blogs.najah.edu/author/emp_2384 An-Najah Blogs :: en-us Mon, 26 Oct 2020 05:19:21 IST Mon, 26 Oct 2020 05:19:21 IST webmaster@najah.edu webmaster@najah.edu Liposomes- and ethosomes-associated distamycins: a comparative study.http://blogs.najah.edu/staff/emp_2384/article/Liposomes--and-ethosomes-associated-distamycins-a-comparative-studyPublished Articles The present article describes a comparative study of the performances of liposomes and ethosomes as specialized delivery systems for distamycin A DA and two of its derivatives Liposomes and ethosomes were prepared by classical methods extruded through polycarbonate filters and characterized in terms of dimensions morphology and encapsulation efficiency It was found that DA was associated with vesicles either liposomes or ethosomes by around 160 while both derivatives of DA showed a percentage of association around 80 in the case of liposomes and around 50 in the case of ethosomes In vitro antiproliferative activity experiments performed on cultured human and mouse leukemic cells demonstrated that vesicles were able to increase the activity of both derivatives of DA In addition it was demonstrated that the aging of both liposomes- and ethosomes-associated distamycin suspensions did not heavily influence the vesicle size while all samples showed a relevant drug leakage with time Moreover according to the different physicochemical characteristics of DA and its derivatives ie log P vesicle-associated DA showed the highest loss of drug with respect to both its derivatives In conclusion the enhancement of drug activity expressed by these specialized delivery systems-associated DD could be interesting to obtain an efficient therapeutic effect aimed at reducing or minimizing toxic effects occurring with distamycins administration 1,3-Dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonistshttp://blogs.najah.edu/staff/emp_2384/article/13-Dipropyl-8-1-phenylacetamide-1H-pyrazol-3-yl-xanthine-derivatives-as-highly-potent-and-selective-human-A2B-adenosine-receptor-antagonistsPublished ArticlesA new series of 13-dipropyl-8-1-phenylacetamide-1H-pyrazol-3-yl-xanthine derivatives has been identified as potent A2B adenosine receptor antagonists The products have been evaluated for their binding affinities for the human A2B A1 A2A and A3 adenosine receptors N-4-chloro-phenyl-2-[3-26-dioxo-13-dipropyl-2367-tetrahydro-1H-purin-8-yl-5-methyl-pyrazol-1-yl] 11c showed a high affinity for the human A2B adenosine receptor Ki = 7 nM and good selectivity A1 A2A A3A2B 140 Synthesis and SAR of this novel class of compounds is presented herein Bioorganic Medicinal Chemistry Volume 16 Issue 5 1 March 2008 Pages 2419-2430 http:dxdoiorg101016jbmc200711058Comparative bioavailability of two cefdinir suspension formulations in middle eastern healthy volunteers after single oral administrationhttp://blogs.najah.edu/staff/emp_2384/article/Comparative-bioavailability-of-two-cefdinir-suspension-formulations-in-middle-eastern-healthy-volunteers-after-single-oral-administrationPublished ArticlesThe aim of this study was to compare the bioavailability after oral administration of the generic Adcef R Suspensiontest 125 mg5 ml cefdinir; CAS 91832-40-5 with that of a commercially available original preparation reference 125 mg 5 ml cefdinir For this purpose a randomized two-way crossover bioequivalence study was performed in 24 healthy male volunteers The Middle Eastern selected volunteers were divided into two groups of 12 subjects One group was treated with the reference standard and the other one with the test with a crossover after the drug washout period of 7 days Blood samples were collected at fixed time intervals and cefdinir concentrations were determined by a validated HPLC assay method The pharmacokinetic parameters AUC0-24 AUC0-infinity C-max T-max K-e and T-12 were determined for both formulations and were compared statistically to evaluate the bioequivalence between the two brands of cefdinir using the statistical model recommended by the FDA The analysis of variance ANOVA did not show any significant difference between the two formulations and 90 confidence intervals Cl fell within the acceptable range for bioequivalence Based on the statistical evaluation it was concluded that the two formulations exhibitFormulation and stability evaluation of 1% w/v oral solution of Bromhexine hydrochloride for veterinary usehttp://blogs.najah.edu/staff/emp_2384/article/Formulation-and-stability-evaluation-of-1-wv-oral-solution-of-Bromhexine-hydrochloride-for-veterinary-usePublished ArticlesPurpose: The aim of this study is to develop bromhexine hydrochloride 1 wv oral solution for veterinary use and to evaluate its stability Methods: Solutions of Bromhexine hydrochloride 1wv were prepared by dissolving bromhexine hydrochloride in benzyl alcohol at 50 C then alcohol 96 vv; Tween 80 and purified water were added The obtained solution was filled in amber glass bottles and the solution was stored at 25 C60 relative humidity RH and at 40 C 75 RH The strengths of bromhexine hydrochloride were determined by High performance liquid chromatographic assay at 0 2 4 6 8 10 12 16 20 and 24 months The concentrations of the drug were directly related to the peak area pH odor color and crystal formation was also monitored Results: The degradation of bromhexine hydrochloride 1 wv oral solution was faster at 40 C75 RH than at 25 C 60 RH No significant differences were found between the initial and final pH value for the solution at the studied conditions No detectable changes in color odor or precipitations were observed for the solutions stored at the upper conditions Conclusions: Bromhexine hydrochloride 1 wv oral solution could be formulated and remains stable for at least 2 years when is stored at 25C 60 RH and for 16 months when stored at 40 C 75 RHChewable Tablets: Is this Dosage Form Well Evaluated by Palestinian Health Professionals?http://blogs.najah.edu/staff/emp_2384/article/Chewable-Tablets-Is-this-Dosage-Form-Well-Evaluated-by-Palestinian-Health-ProfessionalsPublished ArticlesAbstract:To evaluate the scientific knowledge and attitudes of health professionals in Palestine regarding the advantages of chewable tablets in comparison with other related dosage forms Methods: Data was gathered from a questionnaire that was handed out to community pharmacists Physicians Pharmaceutical industry decision makers were also enrolled in this study Data was analyzed using SPSS statistical software program version 110 Results: Both the 149 pharmacists and 111 physicians who participated in this study had very close opinions with regard to the superiority of chewable tablets over the corresponding liquid dosage forms especially when issues of palatability stability dose precision ease of administration portability and safety were mentioned Pharmacists and physicians were uncertain about the higher effectiveness of chewable tablets in comparison with other related dosage forms ie syrups and suspensions which contain the same active ingredients All industrial decision makers thought that the number of chewable tablet formulations present in Palestine is relatively low One third of them believed that this dosage form is not fully evaluated nor well appreciated by pharmacists and doctors About half of them thought that the lack of technology or specialized personnel is the reason behind the poor development of this dosage form Conclusion: The importance of chewable tablets is not completely understood and appreciated by the Palestinian health personnel Pharmaceutical manufacturers should pay more attention to the development and production of chewable tablets due to the obvious advantages of this dosage form Clear and complete information about this dosage form must be provided to pharmacists and physicians by medical representativesRational Design, Synthesis, and Evaluation of Key Analogues of CC-1065 and the Duocarmycinshttp://blogs.najah.edu/staff/emp_2384/article/Rational-Design-Synthesis-and-Evaluation-of-Key-Analogues-of-CC-1065-and-the-DuocarmycinsPublished ArticlesThe design synthesis and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and were conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical reactivity and cytotoxic potency Consistent with projections the 7-methyl-1288a-tetrahydrocyclopropa[c]thieno[32-e]indol-4-one MeCTI alkylation subunit and its isomer 6-methyl-1288a-tetrahydrocyclopropa[c]thieno[23-e]indol-4-one iso-MeCTI were found to be 56 times more stable than the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives 310-fold matching or slightly exceeding the potency of the corresponding DSA derivatives consistent with projections made on the basis of the parabolic relationship Notable of these MeCTI-TMI proved to be as potent as or slightly more potent than the natural product duocarmycin SA DSA-TMI IC50 = 5 vs 8 pM and MeCTI-PDE2 proved to be 3-fold more potent than the natural product CC-1065 MeCPI-PDE2 IC50 = 7 vs 20 pM Both exhibited efficiencies of DNA alkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristic of this class of antitumor agentsChemical Stability of Cefotetan Disodium in 0.9% Sodium Chloride Sterile Saline Solutions and Storage in Polypropylene Syringehttp://blogs.najah.edu/staff/emp_2384/article/Chemical-Stability-of-Cefotetan-Disodium-in-09-Sodium-Chloride-Sterile-Saline-Solutions-and-Storage-in-Polypropylene-SyringePublished ArticlesPurpose: The purpose of this study is to evaluate the stability of 60 mgml Cefotetan disodium CTT in 09 sodium chloride sterile saline solution stored in polypropylene syringes at ambient temperature 25 1C and 5 1C by the use of a stability indicating high performance liquid chromatographic assay method Methods: Solutions of CTT 60 mgml were prepared from commercially available 1 g lyophilized vials in normal saline They were filled into 5-ml polypropylene syringes and stored at ambient and 5C temperatures The strengths of CTT were determined by high performance liquid chromatographic assay after 0 1 2 3 6 12 18 24 and 30 days The concentrations of the drug were directly related to the peak area and the percent relative standard deviation based on 5 concentrations was 09 The initial and final pH values were recorded and compared also the initial and final color of the solution were compared Results: There was at least one decomposition product which was separated from the parent drug The loss in potency was less than 9 after 6 days of storage at ambient temperature while the loss of potency at 5C was less than 2 The pH value increased from 57 to 6 when the injection was stored at 5 C for 30 days The drug was not adsorbed onto the plastic syringes The intensity of the light yellow color was increased during the storage period at ambient temperature but didnt change significantly with storage at 5 C Conclusion: Cefotetan 60 mg ml in normal saline solution stored in polypropylene syringes was stable for 6 days at 25 C and for 24 days when stored at 5 CLiposomes and Micellar Dispersions For Delivery of Benzoheterocyclic Derivatives of Distamycin Ahttp://blogs.najah.edu/staff/emp_2384/article/Liposomes-and-Micellar-Dispersions-For-Delivery-of-Benzoheterocyclic-Derivatives-of-Distamycin-APublished ArticlesIn this article we describe the production and characterization of specialized delivery systems for some distamycin derivatives DD namely liposomes and micellar dispersions All the formulations were designed to increase the solubility of DD in an aqueous environment and to reduce the possible toxicity problems related to the administration of these drugs For instance liposomes were prepared by reverse phase evaporation technique followed by extrusion through polycarbonate filters then characterized in terms of dimensions morphology and encapsulation efficacy The analysis of their in vitro antiproliferative activity on cultured human and mouse leukemic cells demonstrated that liposomes and micellar dispersions containing DD exert quite different effects These effects were compared with those shown by the free drug depending on type of drug and also cell line used Drug Delivery Volume 14 Issue 1 January 2007 pages 1 - 8 http:wwwinformaworldcomopenurl?genre=articleissn=10712d7544volume=14issue=1spage=1Bioequivalence study of two fluoxetine capsule formulations in healthy Middle Eastern volunteershttp://blogs.najah.edu/staff/emp_2384/article/Bioequivalence-study-of-two-fluoxetine-capsule-formulations-in-healthy-Middle-Eastern-volunteersPublished ArticlesObjective: To assess the bioequivalence of two fluoxetine hydrochloride capsule 20 mg formulations Fluoxicare capsule from Pharmocare Ltd Chemicals and Cosmetics Ramallah Palestine as test formulation and Prozac from Eli Lilly Ltd Basingstoke UK as reference formulation Design and methods: The study was conducted open with a randomized 2-period crossover design and a 6-week washout period Participants were 24 healthy male volunteers aged 18 - 28 years divided into 2 groups of 12 subjects One group was given the originator drug reference formulation and the other was given the test formulation Blood samples were obtained at baseline and at 14 time points during the interval 0 - 96 hours after drug administration The concentrations of the samples were assayed spectrophotometrically at 220 nm using a Shimadzu 160 A UV-visible spectrometer We calculated the plasma concentration-time curve AUC maximum plasma concentration C-max and time of maximum plasma concentration tmax for each subject Logarithmic transformation of the AUC and C-max was used for the statistical analyses and to assess the bioavailability of the two formulations using analyses of variance ANOVA and Satherwait t-tests for unequal variances The ANOVA performed Of tmax in C-max and in AUC provided the appropriate intra-subject variance estimates to evaluate the 90 confidence intervals for the differences between study variables after administration of the test and reference formulations Statistical analyses were conducted on AUC0-4 as the extrapolated part of the AUC a truncated area approach was adapted Results: The mean pharmacokinetic parameters for both of the drugs under study were as follows: C-max = 6124 - 1296 ngml for the test formulation and for the reference formulation C-max = 6139 - 141 ngml the effects were statistically equivalent The tmax for the test formulation was 825 - 17 and 733 - 096 for the reference formulation The area under the curve to infinity AUC0-infinity ng dayml for the test formulation and for the reference formulation were 29302 - 5269 and 29615 - 6169 respectively Conclusions: The two formulations had equivalent pharmacokinetic parameters were well-tolerated and their relative bioavailability was 9894Admission blood glucose level as a potential indicator for short-term mortality and morbidity after myocardial infarctionhttp://blogs.najah.edu/staff/emp_2384/article/Admission-blood-glucose-level-as-a-potential-indicator-for-short-term-mortality-and-morbidity-after-myocardial-infarctionPublished ArticlesHyperglycemia is common among patients with acute myocardial infarction AMI and is associated with high risk of mortality and morbidity However the relationship between admission plasma glucose APG levels and mortality in diabetic and nondiabetic patients with AMI needs further investigation The aim of this study was to investigate the relationship between APG level and short-term mortality and morbidity after AMI Materials And Methods : This is a prospective study of 79 consecutive patients with AMI followed up for 90 days Medical history as well as demographic and clinical baseline characteristics of the patients was obtained from Al-Watni Governmental Hospital medical records The patients were divided into four groups based on APG levels Patients\ health status was followed up by phone call interviews with the patients and their families Follow-up data were further confirmed using patients\ medical records at the hospital The phone interviews investigated all causes of death or congestive heart failure CHF or re-infarction Results : The mean age of patients was 619 123 years At the time of hospital admission the median PG level was 162 mgdl During the 3-month follow-up overall mortality was 203 and was increased to 563 in patients with glucose levels 200 mgdl Mortality was comparable 219 vs 191; P 005 between diabetic and nondiabetic patients Nonfatal adverse outcomes in the form of combined CHF and re-infarction were highest in group IV and lowest in group I Conclusion :Our study demonstrates that high APG level is common in patients with AMI and is associated with high risk of mortality and morbidity among patients with or without diabetes mellitus In fact our study showed that nondiabetic patients with high APG have higher risk of mortality than patients with a known history of diabetes mellitus Int J Diab Dev Ctries 2006;26:116-21 Hybrid molecules based on distamycin A as potential antitumor agentshttp://blogs.najah.edu/staff/emp_2384/article/Hybrid-molecules-based-on-distamycin-A-as-potential-antitumor-agentsPublished ArticlesMany natural and synthetic anticancer agents with the ability to interact with DNA have been discovered but most of them have relatively low therapeutic index This is probably related to the fact that these derivatives cause DNA damage in an unspecific manner inducing unselective growth inhibition and death both in neoplastic and in highly proliferative normal tissues For these reasons there has been considerable interest in finding small molecules able to alkylate the DNA with a much higher degree of sequence specificity and to modify the function of nucleic acids irreversibly Analogues of naturally occurring antitumor agents such as distamycin A which bind in the minor groove of DNA represent a new class of anticancer compounds currently under investigation Distamycin A has driven researchers attention not only for the biological activity but also for its non intercalative binding to the minor groove of double-stranded B-DNA where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs The pyrrole-amide skeleton of distamycin A has also been used as DNA sequence selective vehicle for the delivery of alkylating functions to DNA targets leading to a sharp increase of its cytotoxicity in comparison to that very weak of distamycin itself The DNA alkylating and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frameDrug Interactions and Risk of Bleeding among Patients with Atrial ‎Fibrillation (AF) Discharged with Warfarinhttp://blogs.najah.edu/staff/emp_2384/article/Drug-Interactions-and-Risk-of-Bleeding-among-Patients-with-Atrial-lrmFibrillation-AF-Discharged-with-WarfarinPublished ArticlesThe objective of this study was to examine and evaluate the frequency of bleeding and serious drug interactions among patients with atrial fibrillation AF treated with oral anticoagulant [Warfarin] A random sample of 59 patients from Al-Watni government hospital in Nablus with a principal or secondary discharge diagnosis of AF was identified All drug and clinical data were abstracted from the patients files We excluded patients who were less than 65 years of age or left the hospital against medical advice and those whose AF was transient or could not be confirmed Of the original 59 AF patients 19 were cliagnosed who were discharged on Warfarin The mean age for these patients was 717 years Among the patients discharged on Warfarin 947 had one or more drug drug interactions that could lead to increase risk of bleeding Many patients discharged on Warfarin were having multiple interacting drugs Patient counseling and follow-up monitoring are essential and should be carried out to minimize the risk of bleeding and other complications An-Najah University Journal for Research - Natural Sciences A ISSN: 1727-2114 Volume 20 2006 Pages: 127-134New Pyrrolo[2,1-f]purine-2,4-dione and Imidazo[2,1-f]purine-2,4-dione Derivatives as Potent and Selective Human A3 Adenosine Receptor Antagonistshttp://blogs.najah.edu/staff/emp_2384/article/New-Pyrrolo21-fpurine-24-dione-and-Imidazo21-fpurine-24-dione-Derivatives-as-Potent-and-Selective-Human-A3-Adenosine-Receptor-AntagonistsPublished ArticlesCompounds presenting an additional fused ring on the xanthine nucleus have been reported to exhibit antagonistic activity with various levels of affinity and selectivity toward the four adenosine receptors subtypes A1 A2A A2B and A3 This paper reports synthesis and biological evaluation of new 1-benzyl-3-propyl-1H6H-pyrrolo[21-f]purine-24-diones and 1-benzyl-3-propyl-1H8H-imidazo[21-f]purine-24-diones among which we identified potent and selective A3 adenosine receptors antagonists In particular 1-benzyl-7-methyl-3-propyl-1H8H-imidazo[21-f]purine-24-dione 11e shows a Ki hA3 value from binding assay of 08 nM J Med Chem 2005 48 14 pp 46974701 DOI: 101021jm058008c Publication Date Web: June 21 2005New 2-Arylpyrazolo[4,3-c]quinoline Derivatives as Potent and Selective Human A3 Adenosine Receptor Antagonistshttp://blogs.najah.edu/staff/emp_2384/article/New-2-Arylpyrazolo43-cquinoline-Derivatives-as-Potent-and-Selective-Human-A3-Adenosine-Receptor-AntagonistsPublished ArticlesIn this paper we report the synthesis and biological evaluation of a new class of 2-phenyl-25-dihydro-pyrazolo[43-c]quinolin-4-ones as A3 adenosine receptor antagonists We designed a new route based on the Kira-Vilsmeier reaction for the synthesis of this class of compounds Some of the synthesized compounds showed A3 adenosine receptor affinity in the nanomolar range and good selectivity as evaluated in radioligand binding assays at human h A1 A2A A2B and A3 adenosine receptor subtypes We introduced several substituents on the 2-phenyl ring In particular substitution at the 4-position by methyl methoxy and chlorine gave optimal activity and selectivity 6c KihA1 A2A1000 nM EC50hA2B1000 nM KihA3 = 9 nM 6d KihA1 A2A1000 nM EC50hA2B1000 nM KihA3 = 16 nM 6b KihA1 A2A 1000 nM EC50hA2B1000 nM KihA3 = 19 nM In conclusion the 2-phenyl-25-dihydro-pyrazolo[43-c]quinolin-4-one derivatives described herein represent a new family of in vitro selective antagonists for the adenosine A3 receptor DOI: 101021jm050125kDesign, Synthesis, and Biological Evaluation of New 8-Heterocyclic Xanthine Derivatives as Highly Potent and Selective Human A2B Adenosine Receptor Antagonistshttp://blogs.najah.edu/staff/emp_2384/article/Design-Synthesis-and-Biological-Evaluation-of-New-8-Heterocyclic-Xanthine-Derivatives-as-Highly-Potent-and-Selective-Human-A2B-Adenosine-Receptor-AntagonistsPublished ArticlesHere we report the synthesis of 8-heterocycle-substituted xanthines as potent and selective A2B adenosine receptor antagonists The structureactivity relationships SAR of the xanthines synthesized in binding to recombinant human A2B adenosine receptors ARs in HEK-293 cells HEK-A2B and at other AR subtypes were explored The synthesized compounds showed A2B adenosine receptor affinity in the nanomolar range and good levels of selectivity evaluated in radioligand binding assays at human h A1 A2A A2B and A3 ARs We introduced several heterocycles such as pyrazole isoxazole pyridine and pyridazine at the 8-position of the xanthine nucleus and we have also investigated different spacers substituted acetamide oxyacetamide and urea moieties on the heterocycle introduced Various groups at the 3- and 4-positions of phenylacetamide moiety were studied This study allowed us to identify the derivatives 2-34-dimethoxyphenyl-N-[5-26-dioxo-13-dipropyl-2367-tetrahydro-1H-purin-8-yl-1-methyl-1H-pyrazol-3-yl]acetamide 29b MRE2028F20 [KihA2B = 38 nM KihA1hA2AhA3 1000 nM] N-benzo[13]dioxol-5-yl-2-[5-26-dioxo-13-dipropyl-2367-tetrahydro-1H-purin-8-yl-1-methyl-1H-pyrazol-3-yloxy]acetamide 62b MRE2029F20 [KihA2B = 55 nM KihA1hA2AhA3 1000 nM] and N-34-dimethoxyphenyl-2-[5-26-dioxo-13-dipropyl-2367-tetrahydro-1H-purin-8-yl-1-methyl-1H-pyrazol-3-yloxy]acetamide 72b MRE2030F20 [KihA2B = 12 nM KihA1hA2A hA3 1000 nM] which showed high affinity at the A2B receptor subtype and very good selectivity vs the other ARs Substitution of the acetamide with an urea moiety afforded bioisosteric xanthines with good affinity and selectivity comparable to the acetamide derivatives Substitution at the para-position of a 4-benzyloxy group of the phenylacetamido chain enhanced affinity at the A2B receptor [compound 30b KihA2B = 13 nM vs compound 21b KihA2B = 56 nM] but did not favor selectivity The derivatives with higher affinity at human A2B AR proved to be antagonists in the cyclic AMP assay capable of inhibiting the stimulatory effect of NECA 100 nM with IC50 values in the nanomolar range a trend similar to that observed in the binding assay 62b IC50 = 38 nM; 72b IC50 = 46 nM In conclusion the 8-pyrazolo-13-dipropyl-1H-purine-26-dione derivatives described herein represent a new family of selective antagonists for the adenosine A2B receptorSynthesis and biological effects of a new series of 2-amino-3-benzoylthiophenes as allosteric enhancers of A(1)-adenosine receptorhttp://blogs.najah.edu/staff/emp_2384/article/Synthesis-and-biological-effects-of-a-new-series-of-2-amino-3-benzoylthiophenes-as-allosteric-enhancers-of-A1-adenosine-receptorPublished ArticlesNew derivatives of PD 81723 an allosteric enhancer of agonist binding to the A1-adenosine receptor have been synthesized and evaluated in an intact cell assay Compounds 3a 3o and 3p appeared to be more potent than PD 81723 and at a concentration of 01 mu M caused significant reductions of cAMP content of CHO cells expressing the human A1-adenosine receptor Compounds 4e and 4o appeared to be allosteric enhancers at a low concentration and antagonists at a higher concentration whereas compounds 3c 3g 3s and ill appeared to be weak antagonists that are also allosteric enhancers at the: higher concentration of 10 mu M C 2000 Elsevier Science Ltd All rights reservedDNA minor-groove binders: results and design of new antitumor agentshttp://blogs.najah.edu/staff/emp_2384/article/DNA-minor-groove-binders-results-and-design-of-new-antitumor-agentsPublished ArticlesDNA minor-groove binding drugs have been extensively studied in the last years in order to influence the regulation of gene expression in neoplastic disorders by means of specific interactions with DNA bases Pyrrolo[21-c][14]benzodiazepines PBDs CC-1065 and distamycins are three classes of minor-groove alkylating agents which showed interesting cytotoxicity profiles but they cannot be used in humans for various toxicity problems For this reason many groups applied heterocyclic substitutions extensively in order to either modify the reactivity profile or introduce extra interactions within the minor groove thus changing the binding site or modulating the binding sequence C 1999 Elsevier Science SA All rights reservedSynthesis and Anti-HSV-1 Activity of 6 Substituted Pyrazolo[3,4-d]Pyridazin-7-one Nucleosideshttp://blogs.najah.edu/staff/emp_2384/article/Synthesis-and-Anti-HSV-1-Activity-of-6-Substituted-Pyrazolo34-dPyridazin-7-one-NucleosidesPublished Articlesa new series of 6-substituted N1- and N2 --D-ribofuranosyl-pyrazolo[34-d]pyridazin-76H-one derivatives 8a-g 9b-d and 9f-g has been prepared in the aim to explore the structure-activity relationships and improve the antiviral activity of a series of N1-and N2 --D-ribofuranosyl-pyrazolo[43-d]pyrimidin-76H-one derivatives previously reported by us The studied compounds were preliminary tested for their in vitroa antiviral activity against HSV-1 Among them 8f and 9f were found 2 fold more active than those belonging to the parent seriesHeterocyclic analogs of DNA minor groove alkylating agentshttp://blogs.najah.edu/staff/emp_2384/article/Heterocyclic-analogs-of-DNA-minor-groove-alkylating-agentsPublished ArticlesIt is generally accepted that neoplastic transformation is related to genes alteration or oncogene activation In particularDNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA bases moieties Pyrrolo[21-c][lil]benzodiazepine PBDs CC-1065 and distamycins are three classes of minor groove binders which showed interesting cytotoxicity profiles refined through already reviewed processes of SAR studies Among the modifications to the three families of antitumor compounds hererocyclic substitutions have been extensively applied by many groups in order to either modify the reactivity profile or introduce extra interactions within the minor groove thus changing the binding site or modulating the binding sequence The updated material related to these modifications has been rationalised and ordered in order to offer an overview of the argumentSynthesis, solvolytic stability and cytotoxicity of a modified derivative of CPzI, a pyrazole analog of the alkylation subunit of the antitumor agent CC-1065: Effect of the nitrogen substitution on the functional reactivityhttp://blogs.najah.edu/staff/emp_2384/article/Synthesis-solvolytic-stability-and-cytotoxicity-of-a-modified-derivative-of-CPzI-a-pyrazole-analog-of-the-alkylation-subunit-of-the-antitumor-agent-CC-1065-Effect-of-the-nitrogen-substitution-on-the-functional-reactivityPublished ArticlesThe synthesis and the comparative preliminary biological evaluation of a new pyrazole analog 16 of the CC-1065 alkylating unit CPI are described This new derivative showed low cytotoxicity against L1210 murine leukemia IC50 3064 nM with respect to reference compound but contrarily to literature data was found to be more stable to solvolysis than the natural derivative --N-Boc-CPI pH 3 t12 = 212 h vs 37 h The results of such investigation showed that alkylation of the pyrazole nitrogen caused a loss of cytotoxic activity in vitro against tumor cells This experimental observation allowed us to confirm the importance of free N-H for the anticellular activitySynthesis, cytotoxicity and antitumor activity of some new simplified pyrazole analogs of the antitumor agent CC-1065. Effect of an hydrophobic group on antitumor activityhttp://blogs.najah.edu/staff/emp_2384/article/Synthesis-cytotoxicity-and-antitumor-activity-of-some-new-simplified-pyrazole-analogs-of-the-antitumor-agent-CC-1065-Effect-of-an-hydrophobic-group-on-antitumor-activityPublished ArticlesThree simplified pyrazole analogs 7-9 of the antitumor agents CC-1065 were synthesized In in vitro assays against L1210 cell lines all derivatives showed a cytotoxicity in a pM range values close to the natural target compound -CC-1065 In in vivo tests against disseminate L1210 leukemia cells synthesized compounds showed a good potency OD 300 mu gKg but no activity These observations further validate the effect of the hydrophilic andor hydrophobic characteristics of the substituents present on the molecules confirming the relevance of this phenomena on in vivo activity In fact in this case the increase of hydrophobic characteristics of the molecules produce the loss of activity probably due to a worse bioavailability of the drugs in animalsA new synthetic approach to indazole synthesishttp://blogs.najah.edu/staff/emp_2384/article/A-new-synthetic-approach-to-indazole-synthesisPublished ArticlesStobbe condensation of 3-alkyl- or aryl-4-formylpyrazoles 3a-f with diethyl succinate in the presence of potassium t-butoxide followed by intramolecular ring closure Ac2O-NaOAc afforded the corresponding indazole derivatives 5a-f in 65-85 overall yield These compounds are good starting materials for transformation to biologically active molecules such as new pyrazole analogs of the left-hand segment of the potent natural antineoplastic agent CC-1065