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1.
J Org Chem ; 79(16): 7266-76, 2014 Aug 15.
Article in English | MEDLINE | ID: mdl-25051020

ABSTRACT

We report the high-yielding and scalable diastereospecific synthesis of isomeric bicyclo[2.2.1]heptane-7- and -8-oximes and their corresponding C-nitroso derivatives, which are the key intermediates for the synthesis of carbanucleosides. Neither the (C7-R)-nitroso- nor (C8-S)-nitrosobicycloheptane system requires any external base in DMSO-d6 to afford the corresponding oxime, and no reverse isomerization from the oxime to the C-nitroso compound was observed. The conversion of the (C8-S)-nitroso compound to the E/Z-oximes was ∼8 times faster (at 40 °C) than that of the (C7-R)-nitroso derivative. The mechanism involves first-order reaction kinetics for the conversion of either the (C7-R)- or (C8-S)-nitroso derivative to the corresponding E/Z-oximes. The lower rate of conversion of the (C7-R)-nitroso compound to the corresponding oximes compared with that of the (C8-S)-nitroso derivative is attributed to the fact that the acidic H8 ionizing center is two bonds away from the OPMB group on C1 in the latter whereas H7 is three bonds away from the C1 OMe group in the former, making the effect of the electron-withdrawing group on C1 stronger in the latter.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Oxides/chemistry , Oximes/chemistry , Kinetics , Molecular Conformation , Nitroso Compounds/chemistry , Thermodynamics
2.
Bioorg Med Chem Lett ; 23(9): 2750-8, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23518280

ABSTRACT

Here we report identification of new lead compounds based on quinoline and indenoquinolines with variable side chains as antiprotozoal agents. Quinolines 32, 36 and 37 (Table 1) and indenoquinoline derivatives 14 and 23 (Table 2) inhibit the in vitro growth of the Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma brucei rhodesiense subspecies and Leishmania infantum with IC50=0.25 µM. These five compounds have superior activity to that of the front-line drugs such as benznidazole, nifurtimox and comparable to amphotericin B. Thus these compounds constitute new 'leads' for further structure-activity studies as potential active antiprotozoal agents.


Subject(s)
Antiprotozoal Agents/chemical synthesis , Quinolines/chemistry , Amphotericin B/chemistry , Amphotericin B/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Cell Line , Cell Survival/drug effects , Humans , Leishmania infantum/drug effects , Nifurtimox/chemistry , Nifurtimox/pharmacology , Nitroimidazoles/chemistry , Nitroimidazoles/pharmacology , Parasitic Sensitivity Tests , Quinolines/chemical synthesis , Quinolines/pharmacology , Structure-Activity Relationship , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei rhodesiense/drug effects , Trypanosoma cruzi/drug effects
3.
J Org Chem ; 77(21): 9747-55, 2012 Nov 02.
Article in English | MEDLINE | ID: mdl-23062056

ABSTRACT

We report an unusual strain-releasing reaction of 1-mesyloxy-8,7-dimethylbicyclo[2.2.1]heptane (3) by a base-promoted substitution at the chiral C3 followed by spontaneous concerted ring opening involving the most strained C2-C3-C4 bonds (with bond angle 94°) and the C2 bridgehead leading to anti-endo elimination of the C1-mesyloxy group by the conjugate base of adenine or thymine to give two diastereomeric C3'(S) and C3'(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene: 3 → T-4a + T-4b and 3 → A-5a + A-5b. These products have been unambiguously characterized by detailed 1D and 2D NMR (J-coupling constants and nOe analysis), mass, and UV spectroscopy. Evidence has been presented suggesting that the origin of these diastereomeric C3'(S) and C3'(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene from 3 is most probably a rearrangement mechanism of a trigonal bipyramidal intermediate formed in the S(N)2 displacement-ring-opening reaction.


Subject(s)
Bridged Bicyclo Compounds/chemistry , Cyclohexenes/chemistry , Heptanes/chemistry , Mesylates/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure
4.
J Org Chem ; 77(16): 6855-72, 2012 Aug 17.
Article in English | MEDLINE | ID: mdl-22857001

ABSTRACT

Two free-radical cyclization reactions with the radical at the chiral C4 of the pentose sugar and the intramolecularly C1-tethered olefin (on radical precursors 8 and 17) gave a new diastereospecific C4-C8 bond in dimethylbicyclo[2.2.1]heptane 9, whereas the new C4-C7 bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave trans and cis diastereomers, in which the chirality of the C4 center is fully retained as that of the starting material. It has been shown how the chemical nature of the fused carba-pentofuranose scaffolds, dimethylbicyclo[2.2.1]heptane 9 vis-a-vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in the former versus 2-O- in the latter), dictates the stereochemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure 1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the α-face) with that of the 8(R)-CH(2)(•) radical in the ß-face. The conversion of 17 → 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the boat-like transition states is likely.


Subject(s)
Alkenes/chemistry , Free Radicals/chemistry , Heptanes/chemical synthesis , Pentoses/chemistry , Carbohydrate Conformation , Cyclization , Magnetic Resonance Spectroscopy , Stereoisomerism
5.
J Org Chem ; 76(11): 4408-31, 2011 Jun 03.
Article in English | MEDLINE | ID: mdl-21500818

ABSTRACT

Using the intramolecular 5-exo-5-hexenyl radical as a key cyclization step, we previously reported an unambiguous synthesis of carba-LNA thymine (cLNA-T), which we subsequently incorporated in antisense oligonucleotides (AON) and investigated their biochemical properties [J. Am. Chem. Soc.2007, 129 (26), 8362-8379]. These cLNA-T incorporated oligos showed specific RNA affinity of +3.5-5 °C/modification for AON:RNA heteroduplexes, which is comparable to what is found for those of LNAs (Locked Nucleic Acids). These modified oligos however showed significantly enhanced nuclease stability (ca. 100 times more) in the blood serum compared to those of the LNA modified counterparts without compromising any RNase H recruitment capability. We herein report the synthesis of 5-methylcytosine-1-yl ((Me)C), 9-adeninyl (A), and 9-guaninyl (G) derivatives of cLNA and their oligonucleotides and report their biochemical properties as potential RNA-directed inhibitors. In a series of isosequential carba-LNA modified AONs, we herein show that all the cLNA modified AONs are found to be RNA-selective, but the magnitude of RNA-selectivity of 7'-R-Me-cLNA-G (cLNA-G) (ΔT(m) = 2.9 °C/modification) and intractable isomeric mixtures of 7'-(S/R)-Me-cLNA-T (cLNA-T, ΔT(m) = 2.2 °C/modification) was found to be better than diastereomeric mixtures of 7'-(S/R)-Me-cLNA-(Me)C with trace of cENA-(Me)C (cLNA-(Me)C, ΔT(m) = 1.8 °C/modification) and 7'-R-Me-cLNA-A (cLNA-A, ΔT(m) = 0.9 °C/modification). cLNA-(Me)C modified AONs however exhibited the best nuclease stability, which is 4-, 7-, and 20-fold better, respectively, than cLNA-T, cLNA-A, and cLNA-G modified counterparts, which in turn was more than 100 times stable than that of the native. When the modification sites are appropriately chosen in the AONs, the cLNA-A, -G, and -(Me)C modified sites in the AON:RNA hybrids can be easily recognized by RNase H, and the RNA strand of the hybrid is degraded in a specific manner, which is important for the design of oligos for therapeutic purposes. The cLNA-(Me)C modified AON/RNA, however, has been found to be degraded 4 times faster than cLNA-A and G modified counterparts. By appropriately choosing the carba-LNA modification sites in AON strands, the digestion of AON:RNA can be either totally repressed or be limited to cleavage at specific sites or at a single site only (similar to that of catalytic RNAzyme or DNAzyme). Considering all physico- and biochemical aspects of cLNA modified oligos, the work suggests that the cLNA modified antisense oligos have the potential of being a promising therapeutic candidate due to their (i) higher nucleobase-specific RNA affinity and RNA selectivity, (ii) greatly improved nuclease stability, and (iii) efficient RNase H recruitment capability, which can induce target RNA cleavage in a very specific manner at multiple or at a single site, in a designed manner.


Subject(s)
Exonucleases/metabolism , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/metabolism , Oligonucleotides/chemistry , RNA/metabolism , Ribonuclease H/metabolism , Base Sequence , Cyclization , Enzyme Stability , Escherichia coli/enzymology , Humans , Models, Molecular , Molecular Conformation , Nucleic Acid Denaturation , Nucleic Acid Hybridization , Oligonucleotides, Antisense/blood , Oligonucleotides, Antisense/genetics , Organophosphorus Compounds/chemistry , RNA/chemistry , RNA/genetics , Substrate Specificity , Thermodynamics , Transition Temperature
6.
Eur J Med Chem ; 46(4): 1306-24, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21334792

ABSTRACT

Recently we have reported anti-TB properties of a new class of conformationally-constrained indeno[2,1-c]quinolines, which are although considerably active (MIC 0.39-0.78 µg/mL) suffered from intense solubility problems. We thought of improving their bioavailability by prodrugs approach. Accordingly esters of the "Lead" indeno[2,1-c]quinolines 1, 15 and 27 derivatives were synthesized and their prodrug nature at the physiological pH were confirmed. Prodrugs were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MABA assay to show that they have 2- to 4-fold improved anti-TB activities, increased aqueous solubility and superior selectivity index over their respective parent compounds. MIC of these prodrugs was in the range of <0.20-6.0 µg/mL, and in general, no cytotoxicity was observed in VERO cells.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Quinolines/metabolism , Amino Acids/chemistry , Anti-Bacterial Agents/toxicity , Cell Line , Humans , Hydrolysis , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Prodrugs/metabolism , Prodrugs/toxicity , Solubility , Water/chemistry
7.
Org Biomol Chem ; 8(24): 5661-73, 2010 Dec 21.
Article in English | MEDLINE | ID: mdl-20927480

ABSTRACT

Prompted by our discovery of a new class of conformationally-locked indeno[2,1-c]quinolines as anti-mycobacterials, compounds 2a and 3a (Fig. 1; MIC < 0.39 µg mL(-1) and 0.78 µg mL(-1), respectively)(14) with a freely rotating C2-imidazolo substituent, we herein describe the synthesis of pentacyclic azole-fused quinoline derivatives 4 and 5, in which we have restricted the rotation of the C2-imidazolo moiety by fusing it to the adjacent quinoline-nitrogen to give a five-membered fused azole heterocycle. The idea of locking the flexibility of the system by conformational constraint was simply to reduce its entropy, thereby reducing the overall free-energy of its binding to the target receptor. Out of 22 different azole-fused indeno[2,1-c]quinoline derivatives, seven structurally distinct compounds, 9, 15, 17, 25, 27, 28 and 29, have shown 79-99% growth inhibition of Mycobacterium tuberculosis H37Rv at a fixed dose of 6.25 µg mL(-1). The efficacies of these compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of single dose on day one. Of these, two compounds, 9 and 28, inhibited growth of M. tuberculosis very effectively at MIC < 0.39 µg mL(-1) (0.89 µM and 1 µM, respectively). These active compounds 9, 15, 17, 25, 27, 28 and 29 were screened for their cytotoxic effect on mammalian cells (human monocytic cell line U937), which showed that the human cell survival is almost unperturbed (100% survival), except for compound 25, hence these new compounds with new scaffolds have been identified as potent anti-mycobacterials, virtually with no toxicity. Thus these "hit" molecules constitute our important "leads" for further optimization by structure-activity relationship against TB.


Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Azoles/chemistry , Indenes/chemistry , Quinolines/chemical synthesis , Quinolines/pharmacology , Humans , Molecular Structure , Mycobacterium tuberculosis/drug effects , Structure-Activity Relationship , U937 Cells
8.
J Am Chem Soc ; 128(38): 12356-7, 2006 Sep 27.
Article in English | MEDLINE | ID: mdl-16984152

ABSTRACT

tert-Butyldithiomethyl (DTM), a novel hydroxyl protecting group, cleavable under reductive conditions, was developed and applied for the protection of 2'-OH during solid-phase RNA synthesis. This function is compatible with all standard protecting groups used in oligonucleotide synthesis, and allows for fast and high-yield synthesis of RNA. Oligonucleotides containing the 2'-O-DTM groups can be easily deprotected under the mildest possible aqueous and homogeneous conditions. The preserved 5'-O-DMTr function can be used for high-throughput cartridge RNA purification.


Subject(s)
Alkanes/chemistry , RNA/chemical synthesis , Sulfur Compounds/chemistry , Alkanes/chemical synthesis , RNA/isolation & purification , Sulfur Compounds/chemical synthesis
9.
Anal Biochem ; 356(1): 132-41, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16769031

ABSTRACT

A novel, cartridge-based procedure for the efficient and irreversible detritylation of oligonucleotides is reported. This method, combined with a process for the elimination of depurinated fragments produces, in a highly parallel fashion, oligonucleotides with better purity than those traditionally obtained using reversed-phase high-performance liquid chromotography purification. Our combined detritylation and purification methodology compares favorably with commercial cartridge-based purification systems. The benefits of working with pure oligonucleotides, with regard to higher signal and better signal linearity, are shown in array-based hybridization experiments.


Subject(s)
Oligonucleotide Array Sequence Analysis/methods , Oligonucleotides/isolation & purification , Hydrophobic and Hydrophilic Interactions , Oligonucleotide Array Sequence Analysis/statistics & numerical data , Oligonucleotide Probes , Oligonucleotides/chemistry , Reproducibility of Results , Trityl Compounds/chemistry
10.
J Biochem Biophys Methods ; 69(1-2): 179-87, 2006 Nov 30.
Article in English | MEDLINE | ID: mdl-16678272

ABSTRACT

An improved Knoevenagel condensation of 3-isochromanone and aromatic aldehydes can be achieved by microwave irradiation on solid supports in the presence of various catalysts. This synthetic method offers some major advantages, especially the possibility to change the ratio of E/Z isomers.


Subject(s)
Chromones/chemistry , Aldehydes/chemistry , Catalysis , Chromatography, Thin Layer , Chromones/chemical synthesis , Indicators and Reagents , Magnetic Resonance Spectroscopy , Microwaves , Stereoisomerism
12.
J Mol Biol ; 344(5): 1347-58, 2004 Dec 10.
Article in English | MEDLINE | ID: mdl-15561147

ABSTRACT

Human deoxycytidine kinase (dCK) is a key enzyme in the 5'-phosphorylation of purine and pyrimidine deoxynucleosides with deoxycytidine as the most efficient substrate. The ability of dCK to degrade 2'-deoxyribonucleosides to free nucleobases and 2-deoxy-alpha-d-ribofuranose-1-phosphate was demonstrated by 1H-31P correlation spectroscopy and by isotope enzyme kinetic methods. The reaction depended on inorganic phosphate, and dCK showed maximum cleavage activity between pH 7 and pH 8. In this pH range, [HPO4(2-)] is the dominant phosphate species, most likely being the phosphate donor. All natural deoxyribonucleosides could be cleaved and the Vmax of the phosphorylytic reaction compared to the kinase reaction was about 2-10%. The formation of free nucleobases occurred only with reduced dCK, because the reaction was highly dependent on the presence of reducing agents such as dithiotreitol. Thus, recombinant dCK can act as a phosphorylase, similar to the nucleoside phosphorylase family of enzymes. This catalytic activity is important for the design of in vitro experiments with dCK, such as crystallization and NMR spectroscopy.


Subject(s)
Deoxycytidine Kinase/chemistry , Deoxycytidine Kinase/metabolism , Nucleotidases/chemistry , Nucleotidases/metabolism , Catalysis/drug effects , Deoxyribonucleotides/metabolism , Dithiothreitol/pharmacology , Humans , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Molecular Structure , Nucleotides/chemistry , Phosphates/pharmacology , Purines/metabolism , Pyrimidines/metabolism , Substrate Specificity
13.
Nucleosides Nucleotides Nucleic Acids ; 22(12): 2093-104, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14714759

ABSTRACT

A summary delineating the large scale synthetic studies to prepare labeled precursors of ribonucleosides-3',4',5',5''-2H4 and -2',3',4',5',5''-2H5 from D-glucose is presented. The recycling of deuterium-labeled by-products has been devised to give a high overall yield of the intermediates and an expedient protocol has been elaborated for the conversion of 3-O-benzyl-alpha,beta-D-allofuranose-3,4-d2 6 to 1-O-methyl-3-O-benzyl-2-O-t-butyldimethylsilyl-alpha,beta-D-ribofuranose-3,4,5,5'-d4 16 (precursor of ribonucleosides-3',4',5',5''-2H4) or to 1-O-methyl-3,5-di-O-benzyl-alpha,beta-D-ribofuranose-3,4,5,5'-d4 18 (precursor of ribonucleosides-3',4',5',5''-2H4).


Subject(s)
Deuterium/chemistry , Isotope Labeling/methods , Ribonucleosides/chemical synthesis , Glucose/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Ribonucleosides/chemistry
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