Design, Synthesis, Docking Studies and Molecular Dynamics Simulation of New 1,3,5-Triazine Derivatives as Anticancer Agents Selectively Targeting Pancreatic Adenocarcinoma (Capan-1).

On the basis of remarkable anticancer profile of s-triazine nucleus, a new series of 2-methoxy-4-(3-morpholino-5-(arylamino)phenoxy)benzaldehyde derivatives 11 a-u was prepared and evaluated for in vitro antiproliferative activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562 and Z138). Compounds 11 o, 11 r and 11 s were the most potent anticancer agents on pancreatic adenocarcinoma (Capan-1) cell line with IC value of 1.4, 5.

Novel 4-nitroimidazole analogues: synthesis, biological evaluation, studies, and molecular dynamics simulation.

A new series of 4-nitroimidazole bearing aryl piperazines , tetrazole and 1,3,4-thiadiazole derivatives was synthesized. All derivatives were screened for their anticancer activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562, and Z138). Compound proved the most potent compound of the series inhibiting proliferation of most of the selected human cancer cell lines with IC values in the low micromolar range.

New tamoxifen analogs for breast cancer therapy: synthesis, aromatase inhibition and studies.

A new class of tamoxifen analogues, using McMurry reaction conditions, is described. The scheme involved the conversion of ketoprofen () into amide derivatives and , by coupling with -substituted propan-1,3-diamine derivatives in the presence DIC and HOB. Treatment of and with various ketones under McMurry reaction conditions afforded the tamoxifen analogues .

Synthesis, Aromatase Inhibitory, Antiproliferative and Molecular Modeling Studies of Functionally Diverse D-Ring Pregnenolone Pyrazoles.

Background: Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormonedependent breast cancer. Design of new steroidal aromatase inhibitors becomes imperative.

Objective: Synthesis and biological evaluation of two classes of structurally and functionally diverse D-ring pregnenolone pyrazoles as type I aromatase inhibitors and antiproliferative agents.

A novel pregnene analogs: synthesis, cytotoxicity on prostate cancer of PC-3 and LNCPa-AI cells and in silico molecular docking study.

New pregnene analogs of N-hydroxamic acid 6, imino-propane hydrazides 7 and 8 as well as the aryl amides 9-11, oxadiazole, pyrazole and sulfinyl analogs 13-15, via the hydrazide analog 5 of methyl ((5-pregnen-3β,17β-diol-15α-yl)thio)propanoate (4) were synthesized. The in vitro cytotoxic activities of selected synthesized steroids against two human prostate cancer cell lines (PC-3, and LNCaP-AI) were evaluated by MTT assay. Compound 10 was the most active cytotoxic agent among these steroids against PC-3 and LNCaP-AI cell lines with inhibition of 96.

Synthesis of new chiral 1,3,4-thiadiazole-based di- and tri-arylsulfonamide residues and evaluation of in vitro anti-HIV activity and cytotoxicity.

A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a-4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a-2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a-3f. Treatment of 2a-2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a-4w in good yields, together with the unexpected 5.

Synthesis of arylated coumarins by Suzuki-Miyaura cross-coupling. Reactions and anti-HIV activity.

Arylated coumarins were prepared by site-selective Suzuki-Miyaura cross-coupling reaction of the bis(triflate) of 4-methyl-6,7-dihydroxycoumarin. Triarylated coumarins were prepared by Suzuki-Miyaura cross-coupling reactions of 3-bromo-4-methyl-2-oxo-2H-chromene-6,7-diylbis(trifluoromethanesulfonate). The in vitro anti-HIV activity of the products was investigated.

Synthesis and Fluorescence Properties of new Monastrol Analogs Conjugated Fluorescent Coumarin Scaffolds.

A mild and efficient method has been used for the synthesis of ethyl 4-(3-hydroxphenyl)-6-methyl-2-thioxo-1,3-dihydroprimidine-5-carboxylate (monastrol) (2), via Biginelli reaction. Alkylation of 2 with the fluorescent coumarin 3 afforded the new thioether analog 4. Similarly, ethyl 4-(6,8-dichloro-2-oxo-2 H-chromen-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate (6) was prepared.

Synthesis, and Fluorescence Properties of Coumarin and Benzocoumarin Derivatives Conjugated Pyrimidine Scaffolds for Biological Imaging Applications.

Series of coumarin and 5,6-benzomcomarin substituted pyrimidine derivatives 11-15 and 22-25 were synthesized, aiming to develop new imaging fluorescent agents. Analogously, treatment of 4-chloropyrimidine analog 16 with coumarin 3-carbohyrazide 5 under MWI condition followed by boiling with NH4OAc in HOAc furnished coumarin-1,2,4-triazolo-pyrimidine analog 18. The fluorescence property was investigated spectrophotometrically in MeOH with Rhodamine 6G as standard dye.

New biaryl-chalcone derivatives of pregnenolone via Suzuki-Miyaura cross-coupling reaction. Synthesis, CYP17 hydroxylase inhibition activity, QSAR, and molecular docking study.

A new class of steroids is being synthesized for its ability to prevent intratumoral androgen production by inhibiting the activity of CYP17 hydroxylase enzyme. The scheme involved the synthesis of chalcone derivative of pregnenolone 5 which was further modified to the corresponding biaryl-chalcone pregnenolone analogs 16-25 using Suzuki-Miyaura cross-coupling reaction. The synthesized compounds were tested for activity using human CYP17α hydroxylase expressed in Escherichia coli.

A new pregnenolone analogues as privileged scaffolds in inhibition of CYP17 hydroxylase enzyme. Synthesis and in silico molecular docking study.

A new series of 17-(N-(arylimino)-5-pregnen-3β-ol derivatives 19-32 as well as carboxylate and acrylate analogues of pregnenolone 37-40 were synthesized and evaluated for their inhibitory activity against human CYP17 hydroxylase expressed in Escherichia coli. Compounds 32 and 37 were the most potent analogues in this series, showing inhibition activity with IC50 = 2.11 and 1.

New CYP17 hydroxylase inhibitors: synthesis, biological evaluation, QSAR, and molecular docking study of new pregnenolone analogs.

A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5-aryl-1,3,4-thiadiazol-2-yl)-imino-pregnenolone derivatives 11-15 were more active than the sulfonate 24-31 and the ester 37-41 analogs. Derivative 12 showed optimal activity in this series, with IC50 values of 2.

Synthesis of potential pyrimidine derivatives via Suzuki cross-coupling reaction as HIV and kinesin Eg5 inhibitors.

A series of 4-amino-5-((4-chlorophenyl)diazenyl)-6-(alkylamino)-1-methylpyrimidin-2-one derivatives 7-16 were prepared by nucleophilic displacement of 6-chloro-pyrimidine 6 by various amines. 4-Amino-5-((aryl-4-yl)diazenyl)-6-aryl-1-methylpyrimidin-2-one analogs 19-27, as well as 4-amino-5-((aryl-[1,1'-biphenyl]-4-yl)diazenyl)-6-aryl-1-methylpyrimidin-2-one 29-31 and 4-amino-6-aryl-1-methylpyrimidin-2-one 34-34, were synthesized via Suzuki cross-coupling reaction, using Pd(PPh3)4 as a catalyst and arylboronic acids as reagents. All compounds were evaluated for their antiviral activity against the replication of HIV-1 and HIV-2 in MT-4.

Synthesis and antiviral activity of new substituted methyl [2-(arylmethylene-hydrazino)-4-oxo-thiazolidin-5-ylidene]acetates.

A series of new methyl [2-(arylmethylene-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates (5a-o) were synthesized via cyclocondensation of thiosemicarbazones (3a-o) with dimethyl but-2-ynedioate (4) in good yields under solvent-free conditions. The environmentally friendly solvent-free protocol overcomes the limitations associated with the customary protracted solution phase synthesis and afforded the title compounds in a few minutes. Compounds 5b-i and 5h-o were evaluated for their antiviral activity against the replication activity of HIV-1 and HIV-2 in MT-4 using the MTT assay.

Exploration of the in vitro antiviral activity of a series of new pyrimidine analogues on the replication of HIV and HCV.

Background: In continuation of our search for new anti-HIV and anti-HCV agents, the suggestion, synthesis and structure elucidation of a new series of 2,6-diamino-4-alkylthio- or (2-benzylhydrazinyl)-5-p-chlorophenylazopyrimidines), 2,6-diamino-4-(2-benzylhydrazinyl)-5-(aryl-[1,1'-biphenyl]-4-yl)pyrimidines, 2,6-diamino-4-(aryl)-5-(aryl[1,1'-biphenyl]-4-yl) pyrimidines), 6-(aryl)-1,3-dimethyl-5-nitro pyrimidine-2,4-dione and 6-amino-4-methoxy-N,N-dimethyl-6-arylpyrimidines were described.

Methods: The anti-HIV-1 (strain IIIB) and HIV-2 (strain ROD) activity of the newly synthesized pyrimidine analogues was evaluated in vitro in human MT-4 cells using the MT-4/MTT assay. Similarly, the same compounds were evaluated in vitro for their selective antiviral activity against HCV in the Huh 5-2 replicon system (type 1b, Con1 strain).

Synthesis, crystal structure and anti-HIV activity of 2-adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles.

Two series of 2-adamantyl/adamantylmethyl-5-aryl-1,3,4-oxadiazoles (4a-l and 5a-l) were synthesized by cyclodehydration of adamantan-1-carboxylic acid/adamantylacetic acid with various aryl hydrazides (3a-l) in the presence of POCl(3). The synthesis was supported by spectroanalytical techniques and verified further by crystal structure determination of compounds 4e and 5k. The synthesized compounds were screened for their inhibitory activity against HIV-1 and HIV-2 in MT-4 cells.

Synthesis, QSAR and anti-HIV activity of new 5-benzylthio-1,3,4-oxadiazoles derived from α-amino acids.

2-(1-[(4-Chloro/methylphenylsulfonylamino)alkyl]-5-thioxo-4,5-dihydro-1,3,4-oxadiazoles (4a-e) were synthesized, in four steps, via the sulfonyl derivatives of l-amino acids (l-alanine, l-methionine and l-phenylalanine) 1a-e, the esters 2a-e, the hydrazides 3a-e and finally the cyclization to 4a-e. Alkylation of 4a-e with 1.0 mole eq.

Amino acid derivatives, part 4: synthesis and anti-HIV activity of new naphthalene derivatives.

A new series of 2-(naphthalen-2-yloxy)-N-[(aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl] acetamides 5a-f was synthesized from naphthalene-derived glycine derivative 2 via the hydrazinoacetamide analogs 4a-f. Alternatively, treatment of 4a with H(2)SO(4) afforded 2-(naphthalen-2-yloxy)-N-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl) acetamide 6a. Alkylation or sulphonylation of 5a afforded the S-alkylated derivatives 7 and 8, respectively.

Platinum and palladium-triazole complexes as highly potential antitumor agents.

The palladium complexes [(dppe)Pd(L)(2)PdCl(2)], [(dppe)Pd(L)(2)PtCl(2)], [(dppp)Pd(L)(2)PdCl(2)], [(dppm) Pd(L)(2)NiCl(2)], and [(dppm)Pd(L)(2)SnCl(4)] 15-19 were prepared. The antiproliferative activity of the newly synthesized complexes as well as their previously prepared analogues 3-14 and 20-26 were screened against a large panel of human cancer cell lines derived from haematological CD4(+) human T-cells containing an integrated HTLV-1 genome (MT-4). The complex 12a, b exhibited remarkable antiproliferative activity against MT-4, CD4(+) human acute T-lymphoblastic leukemia (CCRF-CEM), human splenic B-lymphoblastoid cells (WIL-2NS), human acute B-lymphoblastic leukemia (CCRF-SB), skin melanoma (SK-MEL-28), and prostate carcinoma (DU145) cell lines (CC(50 )= 0.

Microwave-assisted synthesis of acyclic C-nucleosides from 1,2- and 1,3-diketones.

A simple, rapid and regioselective approach for the synthesis of C-acyclic nucleosides 3, 4, 6, and 9 of dihydropyrimidine, imidazole and indeno[1,2-b]pyridine-9-one derived from 1,2- and 1,3-diketones was performed. By using DMF or pyridine as solvent or bentonite clay as a support, in the presence of TMSTf, ZnCl(2), NH(4)OAc, or NH(4)NO(3), all the desired products were obtained within 5-25 minutes under microwave irradiation (MWI). Acid hydrolysis of 6 and 9 afforded the free acyclic C-nucleosides 7 and 10, respectively.

New sulphonamide and carboxamide derivatives of acyclic C-nucleosides of triazolo-thiadiazole and the thiadiazine analogues. Synthesis, anti-HIV, and antitumor activities. Part 2.

A new series of acyclic C-nucleosides 1',2'-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4] triazolo[3,4-b][1,3,4]thiadiazoles bearing arylsulfonamide (5-8) and arylcarboxamide (9-12) residues have been synthesized under microwave irradiation. Thiadiazines 13-15 have been analogously prepared, and upon acid hydrolysis, afforded the free nucleosides 16-18. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells.

Microwave-assisted synthesis and anti-HIV activity of new acyclic C-nucleosides of 3-(D-ribo-tetritol-1-yl)-5-mercapto-1,2,4-triazoles. Part 1.

Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5-12) and the 6-aryl-thiomethyl analogues 25-27 has been described. Deblocking of 5-12 and 25-27 afforded the free acyclic C-nucleosides 13-20, and 28-30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells.

In vitro antitumor and antiviral activities of new benzothiazole and 1,3,4-oxadiazole-2-thione derivatives.

A series of new benzothiazole derivatives 6a-h have been synthesized, in five steps, from substituted phenols via the 1,3,4-oxadiazole-2-thiones 5a-h. The in vitro antitumor activity of the compounds obtained was investigated and the benzothiazol derivatives 6d and 6e showed strong effects on leukaemia cell lines CCRF-CEM (CC50=12+/-2 micromol L(-1), 8+/-1 micromol L(-1), respectively). These compounds are leading candidates for further development.

In-vitro anti-HIV and antitumor activity of new 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and thiadiazine analogues.

A series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (7-15) and the thiadiazine analogues 16-18 have been synthesized under microwave irradiation (MWI). All synthesized compounds are evaluated for their antiviral activity against the replication of HIV-1 and HIV-2 activity in MT-4. However, compounds 12 and 18 showed EC(50) = 2.

New acyclic quinoxaline nucleosides. Synthesis and anti-hiv activity.

A series of acyclonucleosides substituted 1-(4,5-dihydroxypentyl) (13-8) and 2-(4,5-dihydroxypentyloxy)quinoxalines (19-24) were synthesized by the sharpless asymmetric dihydroxylation of the derivatives 1-6 and 7-12, respectively. Treatment of the quinoxaline base 26 with (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-p-toluenesulfonate (27) in the presence of NaH/DMF furnished 28. Acid hydrolysis of 28 gave 1-(2,3-dihydroxypropyl)-6,7-dimethyl-quinoxaline-2-one (29).