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1.
Org Lett ; 18(5): 1044-7, 2016 Mar 04.
Article in English | MEDLINE | ID: mdl-26882295

ABSTRACT

The synthesis of very long helical aromatic amide foldamers was thought to be limited by steric hindrance associated with stable folded conformations. This difficulty may be overcome by using pure reagents, relatively high concentrations, and long reaction times. Bromine substituents and careful identification and elimination of anhydride byproducts both greatly improve chromatographic purification, giving access to pure products amenable to a segment-doubling synthesis of sequences composed of up to 96 monomers. An efficient one-pot multibromination of helical oligomers is also reported.

2.
J Pharm Biomed Anal ; 107: 488-94, 2015 Mar 25.
Article in English | MEDLINE | ID: mdl-25679093

ABSTRACT

Forced degradation of Ebastine (1-(4-(1,1-dimethylethyl)phenyl)-4-(4-(diphenylmethoxy) piperidin-1-yl)butan-1-one) drug substance in ultraviolet light condition resulted into an unknown significant degradation product. This degradation product was analyzed using a newly developed reverse-phase HPLC, where it was eluted at 2.73 relative retention time to Ebastine peak. UV degradation product was isolated from reaction mass using preparative HPLC and its structure was elucidated using high resolution MS, multidimensional NMR and FTIR spectroscopic techniques. UV degradation product has been characterized as 2-(4-(benzhydryloxy)piperidin-1-yl)-1-(4-(tert-butyl)phenyl)-2-methylcyclopropanol. (1)H and (13)C NMR chemical shift values were generated using computational chemistry for possible two diastereomers (7R10S and 7R10R) and later 7R10R was confirmed (and its enantiomer) as final structure given it showed close agreement with experimental NMR data. Formation of UV degradation product as a recemic mixture was further verified by computational chemistry evaluation, chiral HPLC and polarimetery. To best of our knowledge, this is a novel degradation product which is not discussed at any form of publication yet.


Subject(s)
Butyrophenones/chemistry , Butyrophenones/isolation & purification , Piperidines/chemistry , Piperidines/isolation & purification , Chromatography, High Pressure Liquid/methods , Mass Spectrometry/methods , Spectroscopy, Fourier Transform Infrared/methods , Ultraviolet Rays
3.
Eur J Med Chem ; 83: 569-80, 2014 Aug 18.
Article in English | MEDLINE | ID: mdl-24996143

ABSTRACT

Several rhodanine derivatives (9-39) were synthesized for evaluation of their potential as anticancer agents. Villsmeier cyclization to synthesize aza-aromatic aldehydes, rhodanine derivatives preparation and Knoevenagel type of condensation between the rhodanines and aza-aromatic aldehydes are key steps used for the synthesis of 31 compounds. In vitro antiproliferative activity of the synthesized rhodanine derivatives (9-39) was studied on a panel of six human tumor cell lines viz. HGC, MNK-74, MCF-7, MDAMB-231, DU-145 and PC-3 cell lines. Some of the compounds were capable of inhibiting the proliferation of cancer cell lines at a micromolar concentration. Six compounds are found to be potent against HGC cell lines; compound 15 is found to be active against HGC - Gastric, MCF7 - Breast Cancer and DU145 - Prostate Cancer cell lines; compound 39 is potent against MNK-74; four compounds are found to be potent against MCF-7 cell lines; three compounds are active against MDAMB-231; nine compounds are found to be potent against DU-145; three compounds are active against PC-3 cell lines. These compounds constitute a promising starting point for the development of novel and more potent anticancer agents in future.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Quinolines/chemistry , Rhodanine/chemical synthesis , Rhodanine/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Rhodanine/chemistry
4.
J Pharm Biomed Anal ; 99: 59-66, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25072842

ABSTRACT

Forced degradation of Amlodipine Besylate (AMD) in acidic condition gave rise to a potential unknown impurity. This unknown acid degradation product (ADP) was evaluated using a new-reverse-phase high performance liquid chromatography (HPLC), where it was eluted at 1.24 relative retention time to AMD peak. ADP was isolated using preparative HPLC from degradation mixture. Later, structure of ADP was elucidated using high resolution MS, multidimensional NMR and FTIR spectroscopic techniques, and characterized as ethyl-6-(2-chlorophenyl)-8-methyl-3,4,6,7-tetrahydro-2H-benzo[b][1,4]oxazine-5-carboxylate. The presence of ADP recemic mixture was confirmed by polarimeter and chiral HPLC. Given the complexity associated with ADP generation, single crystal X-ray crystallography technique was used to confirm proposed structure. In addition, reaction mechanism was postulated and confirmed using computational chemistry. To our knowledge, it is a novel impurity and not reported elsewhere.


Subject(s)
Amlodipine/analysis , Antihypertensive Agents/analysis , Benzoxazines/isolation & purification , Drug Contamination , Acids/chemistry , Amlodipine/chemistry , Antihypertensive Agents/chemistry , Benzoxazines/chemistry , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Drug Stability , Magnetic Resonance Spectroscopy , Molecular Conformation , Optical Rotation , Solvents/chemistry , Spectroscopy, Fourier Transform Infrared , Stereoisomerism , Water/chemistry
5.
Eur J Med Chem ; 71: 53-66, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24275248

ABSTRACT

Baylis-Hillman chemistry derived four series of new epalrestat analogues were synthesized. Three structural changes are introduced in these 39 new epalrestat analogues synthesized. All compounds were evaluated for their in vitro aldose reductase inhibitory (ALR) activity. Biological activity data indicates that compounds 6, 16, 19, 28 and 29 are potent and the activity is in the range of reference drug, epalrestat. Molecular modelling studies were performed to understand the binding interactions of these active molecules with the ALR protein. Molecular docking data indicates the key interactions of epalrestat were retained in some of the active compounds whereas some new interactions were noticed for other molecules. The modifications introduced on epalrestat have impact for developing a new-type of ALR inhibitor.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Rhodanine/analogs & derivatives , Thiazolidines/chemistry , Thiazolidines/pharmacology , Aldehyde Reductase/metabolism , Crystallography, X-Ray , Diabetes Complications/drug therapy , Diabetes Complications/enzymology , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Docking Simulation , Rhodanine/chemical synthesis , Rhodanine/chemistry , Rhodanine/pharmacology , Structure-Activity Relationship , Thiazolidines/chemical synthesis
6.
Chemphyschem ; 13(15): 3526-34, 2012 Oct 22.
Article in English | MEDLINE | ID: mdl-22887893

ABSTRACT

We carried out a detailed computational investigation of an earlier experimentally observed, unusual, regioselective, electrophilic halogenation in helically folded quinoline oligoamides. In the experimental studies, halogenation occurred selectively at a given monomer of a foldamer substituted with electron-withdrawing groups at the N terminus, although apparently identical reactive sites were available to react with the incoming electrophile. On the other hand, the selectivity was lost with weakly electron-donating groups. To gain an insight into the regioselective preference of bromination in quinoline foldamers, conceptual DFT was used to calculate the local nucleophilicity index of various foldamers of different sizes and with different substituents, and it was found that the predicted reaction centers were in line with the experimental results. Frontier molecular orbital analysis was used to understand this behavior. A detailed study of the hypothetical linear conformation of the tetramer for comparison with the folded conformation was carried out. In the case of a linear conformer, the HOMO is localized on specific monomers irrespective of substitution, but upon folding delocalization is observed, which is larger for the weakly electron-donating groups when compared with the electron-withdrawing groups. In the case of strongly donating groups there is no delocalization, even upon folding. The behavior remains the same when the size of the helix is increased (octamer). Thus, it is clearly seen in this work that the combined effects of conformations and substituents dictate the regioselectivity in the folded oligoamides; this knowledge will have a profound effect on the field of foldamer chemistry.


Subject(s)
Amides/chemistry , Molecular Conformation , Quantum Theory , Quinolines/chemistry , Stereoisomerism
7.
Eur J Med Chem ; 56: 400-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22926227

ABSTRACT

The present report describes development of a novel, bifunctional molecule possessing both selective antiproliferative activity and siRNA transfection ability. We synthesized a series of cationic lipo-benzamides and screened for in vitro anticancer activities against a panel of cancer and non-cancer cells. The molecule with a ten carbon chain-length (C10M) significantly inhibited proliferation of cancer cells via arresting the cell cycle predominantly in the G1 phase; but did not affect non-cancerous cells. C10M effectively mediated siRNA delivery in vitro. The combined anticancer effect of the delivery of C10M together with its survivin-targeting siRNA cargo was significantly (p < 0.05) superior to that of agent alone. To our knowledge, this is the first report of a dual-purpose molecule with intrinsic anticancer activity and suitability for use in siRNA delivery.


Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Drug Delivery Systems , RNA, Small Interfering/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzamides/chemical synthesis , Benzamides/chemistry , COS Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Gene Silencing/drug effects , Hep G2 Cells , Humans , MCF-7 Cells , Mice , Models, Molecular , Molecular Structure , NIH 3T3 Cells , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 22(18): 6010-5, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22897945

ABSTRACT

Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.


Subject(s)
Cardiotonic Agents/chemical synthesis , Cardiotonic Agents/pharmacology , Heart Failure/drug therapy , Phosphodiesterase 3 Inhibitors/chemical synthesis , Phosphodiesterase 3 Inhibitors/pharmacology , Platelet Aggregation/drug effects , Pyridones/pharmacology , Cardiotonic Agents/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Phosphodiesterase 3 Inhibitors/chemistry , Pyridones/chemistry , Structure-Activity Relationship
9.
J Am Chem Soc ; 130(40): 13210-1, 2008 Oct 08.
Article in English | MEDLINE | ID: mdl-18783218

ABSTRACT

The bromination of helically folded oligoamides of 8-amino-4-isobutoxy-2-quinolinecarboxylic acid by N-bromosuccinimide has been investigated. Bromination occurs preferentially if not exclusively at one position in the sequence despite the presence of multiple, up to seven, a priori comparable, reaction sites. Reactions are up to 2 orders of magnitude faster in a folded octamer than in a short nonhelical dimer, despite the steric hindrance that is expected in a compact folded conformation. The presence of substituents remote from the reaction site have considerable influence, resulting in the loss of regioselectivity, or in the slowing down of the reaction by several orders of magnitude.


Subject(s)
Amides/chemistry , Electrons , Molecular Conformation , Models, Molecular , Quinolones/chemistry
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