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Chapter-5 “Crystal and Molecular Structure Analysis of DP-7: A New Multi Drug Resistance Reverter Lead Molecule” O N H O O The synthesis of this 3,5-Dibenzoyl-4-(3-methoxyphenyl)-1,4-dihydro-2,6-dimethyl pyridine DP7, bearing dibenzoyl groups at C(3) and C(5), respectively, has been achieved by applying the modified Hantzsch-type condensation of 1,3-Diketone (2 equiv) and aromatic aldehydes (1 equiv) using ammonium carbonate as nitrogen source. The product obtained was characterized by spectroscopic techniques & in order to correlate structure activity relationship, the X-ray crystallographic study of DP-7 has been carried out. Publication: [1] Synthesis, Characterization, Crystal and molecular structure analysis of DP-7: A new Multi Drug Resistance Reverter Lead Molecule Cryst. Res. Technol. (2010) Manuscript in preparation.
5.1 Introduction The membrane efflux protein P-glycoprotein, a member of the ATP binding cassette (ABC) family, recognizes and transports structurally, chemically, and armacologically diverse hydrophobic compounds, giving rise to a phenomenon known as multidrug resistance (MDR). Development of MDR is one of the main reasons of failure in cancer chemotherapy, as tumour cells, by increasing drug efflux, acquire cross-resistance to many structurally and functionally unrelated anticancer agents, which therefore never achieve effective intracellular concentrations 1 . In the past few years, extensive studies have been performed with the aim of developing effective chemo sensitizers to overcome MDR of human cancer cells. Potent P-glycoprotein inhibitors have been tested in clinical trials so far, including Ca2+ channel blockers such as verapamil and dihydropyridines 2,3 . However, clinical application of these agents has not been extensively pursued to date, owing to their unwanted and sometimes life threatening cardiovascular side effects such as atria-ventricular block and hypotension. As a consequence, in the last few years, much attention has been focused on congeners of these first generation-MDR inhibitors, in order to develop compounds characterized by appropriate potency and selectivity but also by reduced cardiovascular toxicity. Very recently, 3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7) was proposed as a new MDR reverter. It was found that DP7, at a concentration two order of magnitude higher than its IC50 as a P-glycoprotein inhibitor, was devoid of cardiovascular effects in in vitro rat preparations 4,5 . These data were not considered sufficient evidence of DP7 safety before this drug could be subjected to clinical investigation. Several 1,4 dihydropyridine calcium antagonists are substrate of CYP enzymes. In particular, CYP3A4 metabolizes dihydropyridines into the corresponding pyridines 6 . The dihydropyridine can also inhibit the activity of CYP3A4. For example, Katoh 7 reported that nicardipine, benidipine, maidipine and barnidipine strongly inhibited human CYP3A4 activity, while nivaldipine, nifedipine, nitrendepine and amlodipine exhibited a weak inhibition. The DP-7 was very well explored for variety of biological activity 8 . It was very important to study the X-ray Crystal structure of this molecule which was not studied
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Saurashtra University Re - Accredit
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JANUARY-2011 Statement under O. Ph.
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Acknowledgment This thesis arose in
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since I was a child. My Mother Hans
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CHAPTER - 2 Microwave Assisted Synt
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5.5 Results and discussion 156 5.6
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Ms Mesyl MW Microwave NBS N-bromosu
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1. Microwave Assisted Organic Synth
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1.4 Heating Mechanism In microwave
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1.5. Effects of solvents Every solv
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1.7 Application of microwave in org
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aromatic amines, Lancini’s group
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1.9 2-Aminoimidazole Alkaloids The
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Recently group of Erik 83 described
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1.10 Methods for the preparation of
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R 1 O X R 2 NH 2 H 2N NAc R 1 HN R
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this manifold, was reported in 1925
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Another route to 4(5)-acyl-2-amino-
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this series of compounds against th
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documented. Extra care is needed be
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Very recently the research group of
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OH a,b O N H2N N Boc N 3 H N R N N
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1.12.2 Biofilm Growth Cycle 1) Plan
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can survive both the onslaught of a
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[26] Leadbeater, N. E. (2004) Chemi
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[86] Kreutzberger, A. (1962) J. Org
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Microwave Assisted Synthesis & Stru
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2.1 Introduction As described in ch
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2.3 Proposed Mechanism: Regarding t
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No. 12 60 120 traces 84 a All react
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the development of biofilm related
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In first instance, a series of 2-hy
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Br N N N R 1 OH Br N N N R 1 OH Fig
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do have a very strong effect agains
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2.6 Conclusion In the present study
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2.8 Biological assays 2.8.1 Static
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2.9 Experimental protocol: 2.9.1 Ge
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temperature of 80 °C and a maximum
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29.5,29.4, 29.2, 27.0, 22.6, 14.1.
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Yield: 78 %. 1 H NMR (300 MHz, CDCl
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N Br N N C 14H 29 OH Yield: 72 %. 1
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(75.5 MHz, CDCl3): δ = 167.7, 154.
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N Br N N C 14H 29 OH Cl Yield: 90 %
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2-(3,4-Dichlorophenyl)-2-hydroxy-1-
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N Br N N C 8H 17 OH NO 2 Yield: 49
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C3H7 HN N N H Cl Cl Yield : 70 %. 1
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(s, 1H), 3.16 (s, 3H), 1.80 (m, 2H)
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5-(4’-Nitrobiphenyl-4-yl)-N-octyl
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2.11 Representative NMR spectra 2.1
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2.11.3 10.4329 0.7429 151.5720 10.0
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[21] Matz C, McDougald D, Moreno A.
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Chapter-3 Structure Activity Relati
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imidazoles, where the addition of a
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3.4 Result and Discussion It was fo
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No. H 2N Compound Code N N C8H17 R1
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medium used in the set-up to monito
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H 2N N N N H2N N R R Figure-1 Effec
Page 117 and 118: 3.5.3 Cyclo-alkyl 2-aminoimidazoles
Page 119 and 120: 3.6. Conclusion In the present stud
Page 121 and 122: 3.8. Experimental protocols 3.8.1 G
Page 123 and 124: 122.6, 54.6, 33.3(×2), 27.3 (×2),
Page 125 and 126: Yield: 52 %. 1 H NMR (300 MHz, CDCl
Page 127 and 128: 5-(4-Chlorophenyl)-1-cyclooctyl-1H-
Page 129 and 130: Yield: 50 %. Mp: 76-78 ° C. 1 H NM
Page 131 and 132: 5-(4-Chlorophenyl)-1-cyclobutyl-1H-
Page 133 and 134: Yield: 66%. 1 H NMR (300 MHz, CDCl3
Page 135 and 136: 3.10 Representative NMR spectra 3.1
Page 137 and 138: 3.11 References [1] (a) Alvi K. A,
Page 139 and 140: Copper Catalyzed Microwave Assisted
Page 141 and 142: 4.1 Introduction There are only a f
Page 143 and 144: (Table-1, No- 6). Next reaction tem
Page 145 and 146: No. Product, Yield b (%) No. Produc
Page 147 and 148: 4.4 Possible Mechanism Regarding th
Page 149 and 150: 4.7 Experimental protocols 4.7.1 Ge
Page 151 and 152: Yield: 69 %. 1 H NMR (300 MHz, CDCl
Page 153 and 154: 1-(3-Azidopropyl)-2-(3,4-dichloroph
Page 155 and 156: Yield: 84 %. 1 H NMR (300 MHz, DMSO
Page 161 and 162: 1H), 1.66 (m, 6H), 1.70 (m, 2H). 13
Page 163 and 164: 5.48 Hz, 2H), 3.59 (m, 2H), 3.16 (d
Page 165 and 166: 4.10 References [1] For a general r
Page 167: Crystal and Molecular Structure Ana
Page 171 and 172: oscillation range of 5˚ and proces
Page 173 and 174: C12-C13 1.372(4) C32-C37 1.390(3) C
Page 175 and 176: Fig.-3: Packing of the molecules wh
Page 177 and 178: 1 H NMR (400 MHz CDCl3): δ = 7.57-
Page 179 and 180: 5.9.2 13 C spectra of bs-DP-7
Page 181 and 182: SUMMARY The work represented in the
Page 183 and 184: CONFERENCES/SEMINARS/WORKSHOPS ATTE
Page 185: PUBLICATIONS [1] One-Pot Microwave-
Page 200 and 201: Scheme 2 Competitive formation of 1
Page 202 and 203: Table 2 continued 9 10 11 12 N hydr
Page 204: 8. Colson G, Raboult L, Lavelle F,
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