All Info About Chemistry

Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 16 March 2010

Arthur Y., Shaw , Hao-Han, Liau , Pei-Jung, Lu , Chien-Hsing, Lee , Chia-Ning, Yang , …

The scaffold of 3,5-diaryl-1H-pyrazoles was selected as a molecular template to synthesize novel growth-inhibitory agents in the present study. Our findings suggested that analogs bearing electron-withdrawing groups on one ring while electron-donating groups on another reveal significant activities. In particular, 26bearing a 1,1’-biphenyl moiety displayed the most potent activity against OVCA, SW620, H460 and AGS cells with GI50 values of 0.67, 0.89, 0.73 and 0.79 μM, respectively. The mechanistic study revealed that 26-mediated apoptosis-inducing effect on OVCA cells was, in part, attributed to the inhibition of protein kinase B/Akt activity, accompanied by the mitochondrial apoptotic pathway through the activation of…

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A series of 3,5-diaryl-1H-pyrazoles were synthesized and evaluated for their growth inhibitory activity, apoptosis-inducing effect and structure-activity relationship study.

Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 16 March 2010

Eufrânio N., da Silva , Tiago T., Guimarães , Rubem F.S., Menna-Barreto , Maria do Carmo F.R., Pinto , Carlos A., de Simone , …

In continuing our screening program of naphthoquinone activity against Trypanosoma cruzi, the aetiological agent of Chagas’ disease, new β-lapachone-based 1,2,3-triazoles, 3-arylamino-nor-β-lapachones, 3-alkoxy-nor-β-lapachones and imidazole anthraquinones were synthesised and evaluated against bloodstream trypomastigote forms of the parasite. Compounds 2,2-dimethyl-3-(2,4-dibromophenylamino)-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione, IC50/24 h 24.9 ± 7.4 and 4-azido-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione with 23.4 ± 3.8 μM showed a trypanosomicidal activity higher than benznidazole. These results demonstrate the potential of naphthoquinone derivatives as novel structures for the development of alternative drugs for Chagas’ disease.

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In continuation to our screening program of napththoquinones with activity against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas’ disease, new β-lapachone-based 1,2,3-triazoles, 3-arylamino-nor-β-lapachones, 3-alkoxy-nor-β-lapachones and imidazole anthraquinones were synthesized and evaluated against T. cruzi, with good results

Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 March 2010

Gopal, Sirasani , Tapas, Paul , Rodrigo B., Andrade

Two approaches toward the total synthesis of cytotoxic polyketide natural product (+)- crocacin C (1) are described. The first approach, which was ultimately unsuccessful, was replaced altogether with a second that afforded target 1 in ten linear steps from commercially available Evans’ chiral propionimide (5% overall yield). No protecting groups were utilized in the total synthesis of 1.

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Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 March 2010

Andreas, Nievergelt , Peter, Huonker , Roland, Schoop , Karl-Heinz, Altmann , Jürg, Gertsch

Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT 1A receptor with significant to moderate binding affinities (Ki = 3-20 μΜ. [35S]-GTPγS assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (Ki = 11.6 μg/ml) partially activate the 5-HT 1A receptor (20-60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT 1A active compounds.

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Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 March 2010

Stefania, Terracciano , Simone Di, Micco , Giuseppe, Bifulco , Paola, Gallinari , Raffaele, Riccio , …

In the course of our ongoing efforts to discover new and more effective HDAC inhibitors useful for the development of promising anticancer candidates, we have recently undertaken a molecular modeling study on a small collection of FR235222 analogues, synthesized by us in the frame of a structure-activity relationship investigation, made in order to identify the key structural elements essential for the activity. Progress made in structure elucidation of HDAC active site, together with accurate docking calculations, provided new structural insights useful for a further refinement of the tetrapeptide scaffold which should assure an optimal interaction between the synthetic ligands and…

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New six simplified analogues of the natural cyclotetrapeptide FR235222 were prepared and their biological activities on different HDAC isoforms were evaluated.

Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 March 2010

Savina, Malancona , Monica, Donghi , Marco, Ferrara , Josè I. Martin, Hernando , Marco, Pompei , …

Chronic Hepatitis C Virus (HCV) infections are a significant medical problem worldwide. The NS5B Polymerase of HCV plays a central role in virus replication and is a prime target for the discovery of new treatment options. We recently disclosed 1H-benzo[de]isoquinoline-1,3(2H)-diones as allosteric inhibitors of NS5B Polymerase. Structural and SAR information guided us in the modification of the core structure leading to new templates with improved activity and toxicity/activity window.

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Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 March 2010

Hua, Qin , Chang, Liu , Ying, Guo , Ruiping, Wang , Jianfang, Zhang , …

A series of novel S-DABO analogues (4a1 – 5a12) have been synthesized by an efficient method and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). The biological testing results clearly indicated that the substitution of halogen at the C5 position of pyrimidine ring could increase the anti-HIV-1 RT activity. The most active compounds showed activity in the low micromole range with IC50 values (IC50 0.18-3.03 uM) comparable to nevirapine (IC50 4.12 uM). The docking showed that a new halogen-bond was formed between halogen and carbonyl of TYR188 in the HIV-I RT.

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A halogen bond between the C5-I and the carbonyl of TYR188 could increase the activity to HIV-1 RT.

Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 March 2010

Razieh, Eskandari , Kumarasamy, Jayakanthan , Douglas A., Kuntz , David R., Rose , B. Mario, Pinto

The syntheses of an isomer of kotalanol, a naturally occurring glucosidase inhibitor, and of kotalanol itself are described. The target compounds were synthesized by nucleophilic attack of PMB-protected 1,4-anhydro-4-thio-D-arabinitol at the least hindered carbon atom of two 1,3-cyclic sulfates, which were synthesized from D-mannose. Methoxymethyl ether and isopropylidene were chosen as protecting groups. The latter group was critical to ensure the facile deprotection of the coupled products in a one-step sequence to yield kotalanol and its isomer. The stereoisomer of kotalanol, with the opposite stereochemistry at the C-6’ stereogenic centre, inhibited the N-terminal catalytic domain of intestinal human maltase glucoamylase…

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Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 March 2010

Benjamin J., Mulchin , Christopher G., Newton , James W., Baty , Carole H., Grasso , William John, Martin , …

A variety of 6,7-substituted-5,8-quinolinequinones were synthesised and assessed for their anti-tumour and anti-inflammatory activities, and their ability to inhibit the growth of M. bovis BCG. In particular, the introduction of a sulfur group at the 7-position of the quinolinequinone led to the discovery of two compounds, 6-methylamino-7-methylsulfanyl-5,8-quinolinequinone (10a) and 6-amino-7-methylsulfonyl-5,8-quinolinequinone (12), that exhibited selectivity for leukemic cells over T-cells, a highly desirable property for an anti-cancer drug. A number of anti-inflammatory (AI) compounds were also identified, with 6,7-bis-methylsulfanyl-5,8-quinolinequinone (18a) exhibiting the highest AI activity (0.11 μM), while 6,7-dichloro-5,8-quinolinequinone (7a), 6,7-dichloro-2-methyl-5,8-quinolinequinone (7b), and 6,7-bis-phenylsulfanyl-quinoline-5,8-diol (19) also exhibited good AI activity and…

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6,7-Substituted-5,8-quinolinequinones were synthesised and assessed for their anti-tumour and anti-inflammatory activities, and their ability to inhibit the growth of M. bovis BCG.

Publication year: 2010
Source: Bioorganic & Medicinal Chemistry, In Press, Accepted Manuscript, Available online 15 March 2010

Jay, Lin , Vincent, Roy , Liya, Wang , Li, You , Luigi A., Agrofoglio , …

The pathogenic mycoplasma Ureaplasma parvum (Up) causes opportunistic infections and relies on salvage of nucleosides for DNA synthesis and Up thymidine kinase (UpTK) provides the necessary thymidine nucleotides. The anti-HIV compound 3´-azido-3’-deoxythymidine (AZT) is a good substrate for TK. Methods for a rapid and efficient synthesis of new 3’-α-[1,2,3]triazol-3’-deoxythymidine analogs from AZT under Huisgen conditions are described. Thirteen 3’-analogues were tested with human cytosolic thymidine kinase (hTK1) and UpTK. The new analogs showed higher efficiencies (Km/Vmax values) in all cases with UpTK than with hTK1. Still, hTK1 was preferentially inhibited by 9 out of 10 tested analogs. Structural models of…

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Thirteen 3’-triazolo analogues of AZT were tested on human hTK1 and UpTK of pathogenic mycoplasma Ureaplasma parvum. They are better substrates of UpTK than of hTK1. Structural models of UpTK and hTK1 were constructed to explain the kinetic results and aid future development of anti-mycoplasma nucleosides.