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Saturday, 5 January 2019

Kalyan Kumar Pasunooti, Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Abstract Image
Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.

Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Department of Pharmacology and Molecular Sciences and Department of OncologyJohns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
J. Med. Chem.201861 (24), pp 11158–11168
DOI: 10.1021/acs.jmedchem.8b01252
Publication Date (Web): November 27, 2018
Copyright © 2018 American Chemical Society
*E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955-4520.

■ ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01252. Molecular formula strings (CSV) Detail of synthesis procedures; kinetic curve of CYP3A4 enzyme activities; philipin staining of compound 15c, 15g; competition assay of itraconazole photoaffinity probe; and NMR and HPLC chart of representative compounds (PDF)
■ AUTHOR INFORMATION Corresponding Author *E-mail: joliu@jhu.edu. Phone 410-955-4619. Fax 410-955- 4520. ORCID Wei Q. Shi: 0000-0001-5453-1753 Jun O. Liu: 0000-0003-3842-9841 Author Contributions § Y.L. and K.K.P. contributed equally to this work. Notes The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS This work was supported by the National Cancer Institutes (grant R01CA184103) and the Flight Attendant Medical Research Institute
kp1
str1 str2
4-(4-(4-(4-(((2S,4R)-2-((1H-Tetrazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)- 1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (15n).
1 H NMR (500 MHz, CDCl3, δH): 8.46 (s, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 9 Hz, 2H), 7.24 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.36 (d, J = 14.0 Hz, 1H), 5.27 (d, J = 14.0 Hz, 1H), 4.38 (t, J = 5.0 Hz, 1H), 4.31−4.27 (m, 1H), 3.95 (dd, J = 8.5, 6.5 Hz, 1H), 3.88−3.83 (m, 2H), 3.53 (dd, J = 9.5, 6.5 Hz, 1H), 3.38 (br s, 4H), 3.26 (br s, 4H), 1.89−1.83 (m, 1H), 1.74−1.69 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H).
13C NMR (125 MHz, CDCl3, δC): 162.5, 152.8, 152.7, 152.0, 136.3, 133.9, 133.3, 131.5, 130.1, 129.6, 127.2, 123.6, 116.8, 115.4, 107.4, 74.8, 67.9, 67.6, 56.6, 52.7, 36.5, 31.0, 28.5, 19.2, 10.8.
HRMS (ESI) calcd for C34H37Cl2N9O4, 706.2424; found, 706.2425.
HPLC purity: 95.9%, tR = 10.5 min



Kalyan_Pasunooti2

Kalyan Kumar Pasunooti,

kalyan kumar <kalyandrf@gmail.com>

 
Dr. Kalyan Kumar Pasunooti pursued his PhD degree from Nanyang Technological University (NTU) (www.ntu.edu.sg), Singapore (2007 – 2011) in the field of Medicinal, Peptide & Protein chemistry. His graduate research work is focused on “Synthesis of bioactive amino acid building blocks and their applications towards the peptides and glycopeptides.” His have total 16 years of academic and industry experience with major multinationals companies & academic institutions and have worked with many collaborative professors around the globe. He authored with more than 28 international peer-reviewed high impact publications such as PNAS, Wily (Angew Chemie), RSC (Chem Comm and Org Biomol Chem), most of American Chemical Society journals (Journal of American Chemical SocietyOrg. Lett.ACS Chem BioJ Comb Chem and Bioconugate Chem) and Elsevier (Tetrahedron Letters) journals which are featured many times in Chem. Eng. News and other journals. He holds American patent while work with Johns Hopkins-School of Medicine, USA and this molecule in phase II clinical trials for treating cancer.
Prior to his graduate studies, he spent 5 years as a research scientist in reputable research organizations namely GVK Bio, India (www.gvkbio.com) (2006-2007) and Dr. Reddy’s Laboratories Ltd (www.drreddys.com) (2003-2006) in India. After his PhD graduation, he worked for world leading research institutes such as Johns Hopkins-School of Medicine, USA (www.hopkinsmedicne.org) (2012-2013), Nanyang Technological University-NTU, Singapore) (www.ntu.edu.sg) (2013 – 2017) and Singapore MIT Alliance for research & Technology-SMART (www.smart.mit.edu) (2017–2018). His research interests focused on development of next generation biologically relevant peptide & protein therapeutics using their newly discovered methodologies for biomedical applications.
He has excellent skills in designing synthesis, purification and characterization of complex peptide and small molecules for medicinal chemistry applications. He gained extensive experience in Medicinal, Carbohydrate, Peptide & Protein and nucleotide & nucleoside Chemistry and familiar with modern methods and experienced in designing & executing synthesis for various bioactive peptide and small molecule inhibitors. He well versed in synthesis and characterization of complex organic molecules and with the analytical data interpretation.

Dr. Kalyan Kumar Pasunooti

Research Scientist at Singapore-MIT Alliance for Research & Technology Centre

Singapore’

Accomplished Peptide, Protein and Medicinal chemist with 16 years of academic and industrialexperience in the field of drug discovery and development. Specializations: Peptide & Protein Chemistry,Medicinal Chemistry (Drug Discovery and Development) and Chemical Biology.

ExperienceSingapore-MIT Alliance for Research & Technology Centre

Research Scientist

  • Company NameSingapore-MIT Alliance for Research & Technology Centre

    Dates EmployedJul 2017 – Present

    Employment Duration1 yr 4 mos

    LocationSingapore

    Medicinal Chemistry and Drug Discovery
  • Research Fellow

    Company NameNanyang Technological University, Singapore

    Dates EmployedOct 2013 – Jun 2017

    Employment Duration3 yrs 9 mos

    LocationSingapore

    Peptide & Protein Chemistry and Medicinal Chemistry
  • Postdoctoral Fellow

    Company NameJohns Hopkins Medicine

    Dates EmployedMay 2012 – Sep 2013

    Employment Duration1 yr 5 mos

    LocationBaltimore, Maryland Area

    Medicinal chemistry, Drug Discovery, Pharmacology and Chemical Biology
  • Postdoctoral Associate

    Company NameNanyang Technological University

    Dates EmployedJul 2011 – Mar 2012

    Employment Duration9 mos

    LocationSingapore

    Organic synthesis, Peptide & Carbohydrate chemistry and Medicinal chemistry.
  • Senior Research Associate in Medicinal Chemistry

    Company NameGVK Biosciences

    Dates EmployedJan 2007 – Jul 2007

    Employment Duration7 mos

    LocationHyderabad Area, India

    Synthesis of bioactive molecules for medicinal chemistry applications.
  • Junior Scientist in Medicinal Chemistry (Anti-Infective group)

    Company NameDr. Reddy’s Laboratories

    Dates EmployedAug 2003 – Dec 2006

    Employment Duration3 yrs 5 mos

    LocationHyderabad Area, India

    Medicinal chemistry (Anti-Infective group): My work entails design and synthesis of newoxazolidinone derivatives and new chemical entities as novel antibacterial agents. As a researchscientist my job demanded me to carry out extensive literature survey to design possible syntheticroutes for a proposed molecule and to carry out the total synthetic part in the laborator… See more
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    Monday, 10 December 2018

    (1S,4R)-2-(4-Methoxybenzoyl)bicyclo[2.2.2]octa-2,5-diene

    Capture


    STR1 STR2
    (1S,4R)-2-(4-Methoxybenzoyl)bicyclo[2.2.2]octa-2,5-diene (3a) Yellow liquid (25.2 mg, 95% yield):
    1H NMR (300 MHz, CDCl3)   1.39 (s, 4H, alkyl), 3.77-3.80 (m, 1H, alkyl), 3.85 (s, 3H, OMe), 4.36 (d, J = 5.4 Hz, 1H, alkyl), 6.36 (dd, J = 6.0, 6.0 Hz, 1H, vinyl), 6.46 (dd, J = 6.0, 6.0 Hz, 1H, vinyl), 6.88-6.91 (m, 3H, vinyl + arom.), 7.67 (d, J = 8.3 Hz, 2H, arom.);
    13C{1H} NMR (75 MHz, CDCl3)  = 24.7, 24.8, 37.1, 38.2, 55.4, 113.3, 130.8, 131.5, 133.2, 135.1, 146.5, 147.7, 162.6, 192.3;
    HRMS (ESI-TOF) m/z calculated for C16H16NaO2 [M+Na]+ 263.1048, found 263.1036;
    FT-IR (neat, cm-1 ) 1033, 1174, 1255, 1354, 1600, 1637, 1730, 2870, 2957, 3054.
    Optical Rotation: []D 26 +39.9 (c 2.52, CHCl3) for an enantiomerically enriched sample of 94% ee.
    HPLC analysis (column, CHIRALPAK AD-3, hexane/2-propanol = 98/2, flow rate 1.0 mL/min, 20 C, detection UV 250 nm light); tR of major-isomer 20.7
    Org. Lett.201820 (23), pp 7353–7357
    DOI: 10.1021/acs.orglett.8b02263
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    (1S,4R)-2-(4-Methoxybenzoyl)bicyclo[2.2.2]octa-2,5-diene




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    Sunday, 11 November 2018

    Isosorbide-2-acetate

    str1
    Spectral Data for 1
    MS (ESI): calcd for [M + Na]+, 211.11; found, 211.11.
    IR (KBr) cm–1: 1732.08 (C═O), 3398.57 (−OH).
    1H NMR (400 MHz, CD3OD): δ 5.11 (d, J = 3.6 Hz, 1H), 4.76 (s, 1H), 4.54 (t, J = 4.6 Hz, 1H), 4.49 (d, J = 4.4 Hz, 1H), 4.27 (td, J = 6.7, 5.1 Hz, 1H), 4.01 (dd, J = 10.7, 3.7 Hz, 1H), 3.95 (d, J = 10.7 Hz, 1H), 3.85 (dd, J = 8.8, 6.4 Hz, 1H), 3.50 (dd, J = 8.8, 7.3 Hz, 1H), 2.06 (s, 3H).
    13C NMR (101 MHz, CD3OD): δ 20.8, 73.0, 73.7, 74.3, 80.0, 83.4, 86.9, 171.8.
    Org. Process Res. Dev., Article ASAP
    DOI: 10.1021/acs.oprd.8b00310
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    Tuesday, 9 October 2018

    2-amino-4-bromo-5-fluorobenzoic acid


    Image result for 2-amino-4-bromo-5-fluorobenzoic acid

    STR1 STR2
    2-amino-4-bromo-5-fluorobenzoic acid as a white to off-white crystalline solid
    1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J=9.6 Hz, 1H), 7.21-6.5 (m, 3H), 3.8- 3.3 (br s, 1H).
    13C NMR (100 MHz, DMSO-d6) δ 170.5, 149.6, 147.6, 147.3, 120.4, 118.1, 118.0, 109.2, 109.0, 99.5.
    mp >250 °C. IR (neat) 3494, 3351, 3053, 3038, 1521, 774 cm-1;
    HRMS (ESI) m/z: calcd for C7H5BrFNO2 [M+H]+ 233.9560, found 233.9551.
    Org. Lett.201820 (13), pp 3736–3740
    DOI: 10.1021/acs.orglett.8b01218

    Quetiapine

    Image result for quetiapine
    Quetiapine
    1H NMR (400 MHz, CD3OD): δ = 3.18-3.27 (m, 4H), 3.35-3.44 (m, 3H), 3.56-3.58 (m, 3H), 3.67-3.69 (m, 3H), 3.76 (t, J = 5.2 Hz, 2H), 4.32 (s, 1H), 6.88 (td, J = 7.4 Hz, 1.2 Hz, 1H), 7.04 (dd, J = 7.8 Hz, 1.6 Hz, 1H), 7.13 (td, J = 7.8 Hz, 1.6 Hz, 1H), 7.23 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.28-7.39 (m, 4H) ppm.
    13C NMR (100 MHz, CD3OD): δ = 40.2, 45.6, 52.8, 53.3, 57.6, 62.0, 65.6, 73.4, 123.9, 125.99, 126.0, 128.4, 129.0, 130.6, 131.3, 132.5, 133.2, 134.7, 137.9, 145.7, 170.6 ppm.

    HRMS (ESI+ ): calcd for C21H26N3O2S [M+H]+ 384.1740, found 384.1735.

    STR1
    STR2

    Org. Lett., Article ASAP
    DOI: 10.1021/acs.orglett.8b02812
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    Sunday, 23 September 2018

    3-fluoro-4- morpholinoaniline

    STR1 STR2
    3-fluoro-4- morpholinoaniline
    1H NMR (400MHz, CDCl3)  6.82 (m, 1H, ArH), 6.43 (m, 2H, 2xArH), 3.87 (m, 4H, 2xCH2O), 3.58 (brs, 2H, NH2), 2.99 (m, 4H, 2xCH2N). 13C NMR (100MHz, CDCl3)  156.9 (d J= 245.4Hz), 143.0 (d J=10.4Hz), 131.8 (d J=9.7Hz), 120.4 (d J=4.2Hz), 110.8 (d J=3.0Hz), 104.0 (d J=23.8Hz), 67.3, 51.9 (d J=2.1Hz). HRMS [M] Calcd for C10H13FN2O 196.1006, Found 196.1004.
     
    Org. Process Res. Dev., Article ASAP
    DOI: 10.1021/acs.oprd.8b00153

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