Nucleosides and Nucleotides. 98. Synthesis and Antitumor Activities of 5-Ethynylimidazole-4-carboxamide and -carbonitrile Derivatives

Abstract

5-Ethynyl-1-(2-deoxy-β-D-ribofuranosyl)imidazole-4-carbonitrile (4) and -carboxamide (5) and 5-ethynyl-1-(5-deoxy-β-D-ribofuranosyl)imidazole-4-carbonitrile (11) and -carboxamide (12) have been synthesized from the corresponding 5-iodo derivatives 2 and 7 by a palladium-catalyzed cross-coupling reaction with (tri-methylsilyl)acetylene. The aglycons, 5-ethynylimidazole derivatives 14 and 15 were synthesized by the hydrolytic cleavage of the corresponding nucleosides. The antileukemic activity of these nucleosides and base analogues are also described.     

Synthesis of 2′-Deoxyribonucleoside Derivatives of 1-Deazapurine

Abstract

5, 7-Dichloro-3H-imidazo[4, 5-b]pyridine (4) is a versatile base which can be coupled with a variety of sugar moieties and transformed in a series of 7-alkyl(aryl)amino-derivatives by reacting with the corresponding amines. In this paper synthesis, structure elucidation and ADA inhibitory activity of 2′-deoxyribonucleoside derivatives of N⁶-substituted 1-deazaapurines are described.     

Synthesis and Fluorescent Properties of 6-(4-Biphenylyl)-3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine Analogues of Acyclovir and Ganciclovir

Abstract

Tricyclic (T) analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2) carrying the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system [i.e., 6-(4-BrPh)TACV, 5 and 6-(4-BrPh)TGCV, 6] were transformed into 6-[(4′-R²)-4-biphenylyl] derivatives of TACV (7–9) and TGCV (10–12) by Suzuki cross coupling with 4-substituted phenylboronic acids. Compound 11 (R² = CH₂OH) showed a high (～1000) selectivity index against herpes simplex virus type 1 (HSV-1) together with advantageous fluorescence properties (emission in visible region, little overlap with absorption and moderate intensity).     

Microwave-assisted synthesis of sec/tert-butyl 2-arylbenzimidazoles and their unexpected antiproliferative activity towards ER negative breast cancer cells

A new series of N-sec/tert-butyl 2-arylbenzimidazole derivatives was synthesised in 85–96% yields within 2–3.5?min by condensing ethyl 3-amino-4-butylamino benzoate with various substituted metabisulfite adducts of benzaldehyde under focused microwave irradiation. The benzimidazole analogues were characterised using ¹H NMR, ¹³C NMR, high resolution MS and melting points. Evaluation of antiproliferative activity of the benzimidazole analogues against MCF-7 and MDA-MB-231 revealed several compounds with unexpected selective inhibitions of MDA-MB-231 in micromolar range. All analogues were found inactive towards MCF-7. The most potent inhibition against MDA-MB-231 human breast cancer cell line came from the unsubstituted 2-phenylbenzimidazole 10a.     

Synthesis of various 5-alkoxymethyluracil analogues and structure-cytotoxic activity relationship study

A number of 5-alkoxymethyluracil analogues were synthesized to evaluate their cytotoxic activity. 5-Alkoxymethyluracil derivatives 1 were prepared via known nucleophilic substitution of 5-chloromethyluracil 5 and subsequently transformed to their corresponding nucleosides 2. All prepared compounds were submitted to cytotoxic activity testing against drug sensitive and drug resistant leukaemia cells and solid tumour derived cell lines. In addition, the cytotoxic activity of 5-alkoxymethyluracil analogues 1 and 2 was compared with the previously published 5-[alkoxy(4-nitrophenyl)methyl]uracil analogues 3 and 4. Extensive structure–cytotoxic activity relationship studies are reported.     

Syntheses of 1-[(2-Hydroxyethoxy)methyl]- and 1-[(1,3-Dihydroxy-2-Propoxy)methyl]- Derivatives of 5-Substituted-2,4-difluorobenzene: Unnatural Acyclo Thymidine Mimics for Evaluation as Anticancer and Antiviral Agents

Abstract

A group of 1-[(2-hydroxyethoxy)methyl]- (12) and 1-[(1,3-dihydroxy-2-propoxy)methyl]- (13) derivatives of 2,4-difluorobenzene possessing a variety of C-5 substituents (R = Me, H, I, NO₂) were designed with the expectation that they may serve as acyclic 5-substituted-2′-deoxyuridine (thymidine) mimics. Compounds 12 and 13 (R = Me, H, I) were inactive as anticancer agents (C₅₀ = 10^?3 to 10^?4 M range), whereas the 5-nitro compounds (12d, 13d) exhibited weak-to-moderate cytotoxicity (CC₅₀ = 10^?5 to 10^?6 M range) against a variety of cancer cell lines. All compounds prepared (12a-d, 13a-d) were inactive as antiviral agents in a broad-spectrum antiviral screen that also included the human immunodeficiency virus (HIV-1 and HIV-2) and herpes simplex virus (HSV-1 and HSV-2).     

Synthesis,Antitumor, and DNA Binding Behavior of Novel 4-(2-Hydroxyquinolin-3-yl)-6-Phenyl-5, 6 Dihydropyrimidin Derivatives in Aqueous Medium

This article deals with the synthesis of 4-(2-hydroxyquinolin-3-yl)-6-phenyl-5,6-dihydropyrimidin derivatives (2a–f), on condensation with various aromatic aldehydes and ketones in aqueous ethanolic NaOH solution yielding the corresponding chalcones (3). These chalcones were further reacted with thiourea/urea in the presence of a base, which led to the formation of the titled derivatives (2a–f). The newly synthesized heterocyles were characterized by elemental analysis, FTIR, ¹HNMR, and electronic and mass spectral data. The compounds (2a and 2b) were evulated for in vitro cyctotoxicity against human breast adenocarcinoma cell (MCF-7). In MTT cytotoxicity studies, both quinolinde derivatives were found most effective. The binding interaction behavior of the compound (2a) and (2d) with calf thymus-DNA (CT-DNA) was studied by electronic spectra, viscosity measurements, and thermal denaturation studies. On binding to CT-DNA, the absorption spectrum underwent bathochromic and hypochromic shifts. The binding constant (K_b) observed 4.3 × 10⁵ M^?1 for (2a), and 3.8 × 10⁵ M^?1 for (2d) suggested that compound (2a) binds more strongly with base pairs than (2d).     

Synthesis and biological evaluation of novel 7-hydroxy-4-phenylchromen-2-one–linked to triazole moieties as potent cytotoxic agents

A new series of novel 7-hydroxy-4-phenylchromen-2-one (1a)–linked 1,2,4-triazoles were synthesised using a click chemistry approach. All derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) cytotoxicity screening against a panel of six different human cancer cell lines (AGS, MGC-803, HCT-116, A-549, HepG2, and HeLa) to assess their cytotoxic potential. Among the tested molecules, some of the analogues showed better cytotoxic activity than that shown by the 7-hydroxy-4-phenylchromen-2-one (1a). Of the synthesised 1,2,4-triazoles,the 7-((4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-phenyl-2H-chromen-2-one (4d) showed the best activity, with an IC₅₀ of 2.63?±?0.17?µM against AGS cells. Further flow cytometry assays demonstrated that compound 4d exerts its antiproliferative effects by arresting cells in the G2/M phase of the cell cycle and by inducing apoptosis. Collectively, our results indicate that the 1,2,4-triazole derivatives have a significantly stronger antitumour activity than 1,2,3-triazole derivatives. Most of the compounds exhibited better antitumour activity than the positive control drug 5-fluorouracil.     

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by ¹H NMR, ¹³CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1–S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1–S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with K_is in the range of 1.79?±?0.22–2.73?±?0.08?nM against hCA I and in the range of 1.72?±?0.58–11.64?±?5.21?nM against hCA II, respectively.     

Synthesis of Uridylyl (3′-5′) Uridine Derivatives Containing 5-(Methylamino-Methyl) Uridine as A Modified Nucleoside Found from E. COLI Minor tRNAArg

Abstract

5-(Methylaminomethyl)uridine-containing uridylyl (3′-5′) uridine derivatives (14, 26, and 29), which were the original and modified sequences corresponding to the first letter (position 34) and the 5′-upper ribonucleoside (position 33) in the anticodon loop of minor tRNA^Arg, have been synthesized via 5-(methylaminomethyl)uridine derivatives (4 and 24).     

7-Methylguanosine monophosphate analogues with 5′-(1,2,3-triazoyl) moiety: Synthesis and evaluation as the inhibitors of cNIIIB nucleotidase

The hydrolysis of nucleoside 5′-monophosphates to the corresponding nucleosides and inorganic phosphate is catalysed by 5′-nucleotidases, thereby contributing to the control of endogenous nucleotide turnover and affecting the fate of exogenously delivered nucleotide- and nucleoside-derived therapeutics in cells. A recently identified nucleotidase cNIIIB shows preference towards 7-methylguanosine monophosphate (m⁷GMP) as a substrate, which suggests its potential involvement in mRNA degradation. However, the extent of biological functions and the significance of cNIIIB remains to be elucidated. Here, we synthesised a series of m⁷GMP analogues carrying a 1,2,3-triazole moiety at the 5′ position as the potential inhibitors of human cNIIIB. The compounds were synthesised by using the copper-catalysed azide-alkyne cycloaddition (CuAAC) between 5′-azido-5′-deoxy-7-methylguanosine and different phosphate or phosphonate derivatives carrying terminal alkyne. The analogues were evaluated as cNIIIB inhibitors using HPLC and malachite green assays, demonstrating that compound 1a, carrying a 1,2,3-triazoylphosphonate moiety, inhibits cNIIIB activity at micromolar concentrations (IC₅₀ 87.8?±?7.5?µM), while other analogues showed no activity. In addition, compound 1d was identified as an artifical substrate for ^HscNIIIB. Further characterization of inhibitor 1a revealed that it is poorly recognised by other m⁷G-binding proteins, eIF4E and DcpS, indicating its selectivity towards cNIIIB. The first inhibitor (1a) and unnatural substrate (1d) of cNIIIB, identified here, can be used as molecular probes for the elucidation of biological roles of cNIIIB, including the verification of its proposed function in mRNA metabolism.     

Unraveling the stability of plasma proteins upon interaction of synthesized uridine products: biophysical and molecular dynamics approach

Abstract

Most of the drugs binding to human serum albumin (HSA) are transported to various parts of the body. Here, we have studied the molecular interaction between HSA and synthesized uridine derivatives, 1-[(3R, 4S, 5?R)-2-methyl-3, 4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dion.)(C-MU); [(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl] methyl methyl phosphochloridate (CM-MU) and [(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-2-methyl-3,4-dihydroxyoxolan-2-yl] methyl dihydrogen phosphate (P-MU). Cytotoxic studies of these synthesized compounds with mouse macrophages (RAW 246.7) and HeLa cells (human cervical cancer cells) and binding mechanism of these uridine derivatives with HSA were performed. Subsequently, fluorescence quenching was observed upon titration of uridine derivatives with HSA via static mode of quenching, and the binding constants (K_2-C-MU = 4?±?0.03?×?10⁴M^?1, K_5-CM-MU = 1.95?±?0.03?×?10⁴ M^?1 and K_5-P-MU =1.56?±?0.03?×?10⁴ M^?1) were found to be in sync with the computational results. Further, molecular displacement and molecular docking data revealed that all the derivatives are binding in the subdomain IIA and IIB regions of HSA. The protein secondary structure of complexes was determined by circular dichroism, indicating partial unfolding of the protein upon addition of the uridine derivatives. Furthermore, atomic force microscopy data reveal the change in topology upon binding of 2-C-MU, 5-CM-MU and 5-P-MU with HSA, indicating change in the microenvironment around tryptophan region. Additionally, cytotoxicity studies on HeLa and Raw Cell lines suggested that these molecules have significant anti-proliferative and anti-inflammatory properties. Hence, the study may be of help for development of new drugs based on uridine derivatives which may be helpful for combating various potential diseases.

Communicated by Ramaswamy H. Sarma     

Hybrid α/β-peptides: For-Met-Leu-Phe-OMe analogues containing geminally disubstituted β2,2- and β3,3-amino acids at the central position

Summary. The two fMLF-OMe analogues For-Met-β³hAc₆c-Phe-OMe (6) and For-Met-β²hAc₆c-Phe-OMe (12) and their corresponding N-Boc derivatives 5 and 11 have been synthesized and their biological activity towards human neutrophils evaluated. The N-formyl peptides 6 and 12 exhibit good activity as chemoattractans and 12 is highly active in superoxide anion production. The preferred solution conformation of the two N-formyl derivatives has been discussed.     

Synthesis of Derivatives of 3-Methylxantheve and 1-Methyl-3-Isobutylxanthine 7-β-D-Ribofuranosides

Abstract

Methods of synthesis of 7–(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-8-chloro-3-methylxanthine (5a) and l-methyl-3-isobutylxanthine (5b) were reported. Further nucleophilic displacement of chlorine has provided the corresponding 8-alkylamino and 8-benzylamino derivatives (6a,b-9a,b). Several 5′-acyl analogues of 3-methylxanthine-7–β-D-ribofuranoside (15–18) were synthesized using 7–(2′,3′-di-O-isopropylidene-β-D-ribofuranosyl)-3-methylxanthine (10) as intermediate.     

The synthesis of (Z)-4-oxo-4-(arylamino)but-2-enoic acids derivatives and determination of their inhibition properties against human carbonic anhydrase I and II isoenzymes

The synthesis of (Z)-4-oxo-4-(arylamino)but-2-enoic acid (4) derivatives containing structural characteristics that can be used for the synthesis of several active molecules, is presented. Some of the butenoic acid derivatives (4a, 4c, 4e, 4i, 4j, 4k) are synthesized following literature procedures and at the end of the reaction. In addition, structures of all synthesized derivatives (4a–4m) were determined by ¹H-NMR, ¹³C-NMR and IR spectroscopy. Carbonic anhydrase is a metalloenzyme involved in many crucial physiologic processes as it catalyzes a simple but fundamental reaction, the reversible hydration of carbon dioxide to bicarbonate and protons. Significant results were obtained by evaluating the enzyme inhibitory activities of these derivatives against human carbonic anhydrase hCA I and II isoenzymes (hCA I and II). Butenoic acid derivatives (4a–4m) strongly inhibited hCA I and II with K_is in the low nanomolar range of 1.85?±?0.58 to 5.04?±?1.46?nM against hCA I and in the range of 2.01?±?0.52 to 2.94?±?1.31?nM against hCA II.     

Synthesis of N6-Substituted 9-[3-(Phosphonomethoxy)Propyl]Adenine Derivatives As Possible Antiviral Agents

A number of N ⁶ -substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives having hydroxymethyl at C-1′-position were prepared from the appropriate 6-chloroadenine derivative. The syntheses of the corresponding prodrugs of these compounds are also reported. These compounds showed poor activity against HCV in replicon assay.     

Synthesis of Methylene-Bridged Analogues of Nicotinamide Riboside,Nicotinamide Mononucleotide and Nicotinamide Adenine Dinucleotide

Abstract

5-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-3(R)-(nicotinamid-2-ylmethyl)-α-D-ribofuranose (11a) and ?3(R)-(nicotinamid-6-ylmethyl)-α-D-ribofuranose (11b) were prepared by condensation of 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-erythro-3-pentulofuranose (10) with lithiated (LDA) 2-methylnicotinamide and 6-methylnicotinamide, respectively, and then deprotected to give 1,2-O-isopropylidene-3-(R)-(nicotinamid-2-ylmethyl)-α-D-ribofuranose(12a) and 1,2-O-isopropylidene-3(R)-(nicotinamid-6-ylmethyl)-α-D-ribofuranose (12b). Benzoylation as well as phosphorylation of compounds 12 afforded the corresponding 5-O-benzoate (13b) and 5-O-monophosphates (14a and 14b). Treatment of 13b with CF₃COOH/H₂O caused 1,2-de-O-isopropylidenation with simultaneous cyclization to the corresponding methylene-bridged cyclic nucleoside - 3′,6-methylene-1-(5-O-benzoyl-β-D-ribofuranose)-3-carboxamidopyridinium trifluoro-acetate (8b) - restricted to the “anti” conformation. In a similar manner compounds 14a and 14b were converted into conformationally restricted 2,3′-methylene-1-(β-D-ribofuranose)-3-carboxamidopyridinium-5′-monophosphate (9a - “syn”) and 3′,6-methylene-1-(β-D-ribofuranose)-3-carboxamido -pyridinium-5′monophosphate (9b - “anti”) respectively. Coupling of derivatives 12a and 12b with the adenosine 5′-methylenediphosphonate (16) afforded the corresponding dinucleotides 17. Upon acidic 1,2-de-O-isopropylidenation of 17b, the conformationally restricted P¹-[6,3′-methylene-1-(β-D-ribofuranos-5-yl)-3-carboxamidopyridinium]-P²-(adenosin-5′-yl)methylenediphosphonate 18b -“anti” was formed. Compound 18b was found to be unstable. Upon addition of water 18b was converted into the anomeric mixture of acyclic dinucleotides, i. e. P¹-[3(R)-nicotinamid-6-ylmethyl-D-ribofuranos-5-yl]-P²-(adenosin-5′-yl)-methylenediphosphonate (19b). In a similar manner, treatment of 17a with CF₃COOH/H₂O and HPLC purification afforded the corresponding dinucleotide 19a.

     

Synthesis and Biological Activity of Modified Thiopyrimidine Nucleosides

Abstract

N³ -β-D-glucopyranosyl, galactopyranosyl and xylopyranosyl 6-methyl-2-methylthiouracil and their 5-bromo derivatives have been synthesized by coupling an a-acetobromosugar with the corresponding thiouracil. The new modified thiouridine analogues were evaluated for their inhibitory activity against Human Immunodeficiency Virus (HIV) replication in MT-4 cells as well as for their cytotoxicity.