AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Total synthesis of a thromboxane receptor antagonist, terutroban

 Uncategorized  Comments Off on Total synthesis of a thromboxane receptor antagonist, terutroban
Feb 252015
 

Terutroban acid skeletal.svg

TERUTROBAN

UNII-A6WX9391D8, S18886, S 18886, 165538-40-9, triplion, Terutroban [INN]
Molecular Formula:C20H22ClNO4S
Molecular Weight:407.91098 g/mol
3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid

Terutroban is an antiplatelet agent developed by Servier Laboratories. as of|2008, it is tested for the secondaryprevention of acute thrombotic complications in the Phase III clinical trial PERFORM.

Method of action

Terutroban is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced plateletaggregation and vasoconstriction.

Paper

Total synthesis of a thromboxane receptor antagonist, terutroban

Org. Biomol. Chem., 2015, 13,2951-2957
DOI: 10.1039/C4OB02302A, Paper
*Corresponding authors
aDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India 500 007
E-mail: srivaric@iict.res.in;
Fax: +91-40-27160152 ;
Tel: +91-40-27193210, 27193434
bAcademy of Scientific and Innovative Research, New Delhi, India
Org. Biomol. Chem., 2015,13, 2951-2957

DOI: 10.1039/C4OB02302A

3-(6-(4-Chlorophenylsulfonamido)-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid (2).
…………………….deleted……………………… to give terutroban (2) (1.12 g, 82%) as a white solid.
………………………………………………………
 1H NMR (300 MHz, DMSO-d6) 
δ 7.91 (d, J = 6.6 Hz, 1H),
7.84 (d, J = 8.5 Hz, 2H),
7.66 (d, J = 8.5 Hz, 2H),
6.87 (d, J = 7.7 Hz, 1H),
6.69 (d, J = 7.7 Hz, 1H),
3.31(m, 1H),
2.83–2.65 (m, 4H),
2.63–2.54 (m, 2H),
2.30–2.21 (m, 2H),
2.19 (s, 3H),
1.86–1.74 (m, 1H),
1.63–1.50 (m, 1H); 
……………………………………………………………………….
13C NMR (75 MHz, DMSO-d6) 
δ 174.2, –C=O-OH
140.7,
137.3,
136.9,
133.5,
133.3,
131.9,
129.5,
128.5,
127.9,
127.1,
49.0,
36.4,
32.9,
29.5,
24.3,
24.2,
19.2; -CH3
IR (KBr): νmax 2924, 1709, 1219, 772 cm−1;
HRMS (ESI): Calcd for C20H23O4NClS 408.1030 [M + H]+, found 408.1040.
[Reported 1H NMR  ref a (DMSO-d6) δ 12.5 (s, 1H), 7.9 (s, 1H), 7.8 (d, 2H), 7.7 (d, 2H), 6.9–6.7 (d, 2H), 3.3 (m, 1H), 3.0–2.5 (m, 6H), 2.3 (m, 2H), 2.2 (s, 3H), 2.0–1.5 (m, 2H).]
a   (a) B. Cimetière, T. Dubuffet, O. Muller, J.-J. Descombes, S. Simonet, M. Laubie, T. J. Verbeuren and G. Lavielle, Bioorg. Med. Chem. Lett., 1998, 8, 1375
Synthesis of terutroban (2) is achieved following a non-Diels-Alder approach using cost-effective chemicals.
PREDICTIONS
CAS NO. 165538-40-9, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid H-NMR spectral analysis
3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid NMR spectra analysis, Chemical CAS NO. 165538-40-9 NMR spectral analysis, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid H-NMR spectrum
CAS NO. 165538-40-9, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid C-NMR spectral analysis
3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid NMR spectra analysis, Chemical CAS NO. 165538-40-9 NMR spectral analysis, 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid C-NMR spectrum
EXTRA INFO

Terutroban is an antiplatelet agent developed by Servier Laboratories. It has been tested for the secondary prevention of acute thrombotic complications in the Phase III clinical trial PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack).[1] The study was prematurely stopped and thus it could not be determined whether terutroban has a better effect than aspirin.

Method of action

Terutroban is a selective antagonist of the thromboxane receptor. It blocks thromboxane induced platelet aggregation andvasoconstriction.[2][3]

 

…………………..

 

10.1358/dof.2006.031.10.1038241

 

Thromboxane A2 (TxA2) is an unstable metabolite of arachidonic acid formed by the cyclooxygenase pathway and released from activated platelets, monocytes and damaged vessel walls, causing irreversible platelet aggregation, vasoconstriction and smooth muscle cell proliferation. From efforts to discover novel compounds that could block the deleterious actions of TxA2, the 2-aminotetralin derivative terutroban sodium (S-18886) emerged as a potent, orally active, long-acting, selective antagonist of thromboxane (TP) receptors. The agent was able to inhibit TP agonist-induced platelet aggregation and vasoconstriction and was selected for further development as an antiplatelet and antithrombotic agent. Terutroban has been shown to be effective in animal models of thrombosis, atherosclerosis and diabetic nephropathy and is currently undergoing phase III development for the secondary prevention of acute thrombotic complications of atherosclerosis.

 

 

References

  1.  Hennerici, M. G.; Bots, M. L.; Ford, I.; Laurent, S.; Touboul, P. J. (2010). “Rationale, design and population baseline characteristics of the PERFORM Vascular Project: an ancillary study of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) trial”. Cardiovascular Drugs and Therapy24 (2): 175–80. doi:10.1007/s10557-010-6231-2. PMC 2887499. PMID 20490906. edit
  2.  H. Spreitzer (January 29, 2007). “Neue Wirkstoffe – Terutroban”. Österreichische Apothekerzeitung (in German) (3/2007): 116.
  3.  Sorbera, LA, Serradell, N, Bolos, J, Bayes, M (2006). “Terutroban sodium”. Drugs of the Future 31 (10): 867–873.doi:10.1358/dof.2006.031.10.1038241
Terutroban
Terutroban acid skeletal.svg
Systematic (IUPAC) name
3-((6R)-6-{[(4-Chlorophenyl)sulfonyl]amido}-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid
Clinical data
Legal status
  • Investigational
Routes Oral
Pharmacokinetic data
Half-life 6–10 hours
Identifiers
CAS number 165538-40-9 
609340-89-8 (sodium salt)
ATC code None
PubChem CID 9938840
ChemSpider 8114465 
UNII A6WX9391D8 
Chemical data
Formula C20H22ClNO4S 
Molecular mass 407.911 g/mol

 

 

Srivari Chandrasekhar

Chief Scientist & Head, Division of Natural Products Chemistry, CSIR- Indian Institute of Chemical Technology

Chandrasekhar obtained his Bachelor’s and Master’s degrees in 1982 and 1985 respectively, from Osmania University, Hyderabad and excelled in the same with distinction. He then joined A. V. Rama Rao’s group at CSIR–IICT and earned his doctorate in 1991, also from Osmania University. Between 1991 and 1994 he was associated with J. R. Falck (University of Texas Southwestern Medical Center) as a postdoctoral student. In 1994, Chandrasekhar joined his parent institute (CSIR–IICT) as a scientist

Tarnaka, Hyderabad, India 500 007

srivaric@gmail.com

 

READ………..http://www.currentscience.ac.in/Volumes/108/02/0160.pdf

Council of Scientific and Industrial Research
Ministry of Science and Technology, Government of India
CSIR-IICT
CSIR-Indian Institute of Chemical Technology





http://www.iictindia.org

 


Chandrasekhar obtained his Bachelor’s and Master’s degrees in 1982 and 1985 respectively, from Osmania University, Hyderabad
After obtaining a Ph.D. under the supervision of Dr. A. V. Ramarao at the Indian Institute of Chemical Technology, Hyderabad,
DR AV RAMA RAO
He moved to theUniversity of Texas Southwestern Medical School for post-doctoral research with Professor J. R. Falck
Professor J. R. Falck
and
then to the University of Goettingen, Germany as Alexander von Humboldt Fellow in the group of Professor L. F. Tietze.
 Professor L. F. Tietze
His research interests include the synthesis of marine natural products, peptides and peptidomimetics, combinatorial chemistry and new solvent media for organic synthesis.
He is a recipient of a Young Scientist award of the Indian National Science Academy, B M Birla Science Prize and National Academy of Sciences-Reliance Industries Platinum Jubilee Award. He has over 190 publications, 2 patents, and guided 20 students for their Ph.D. degrees. Presently he is a deputy director at the Indian Institute of Chemical Technology where he supervises a group of 30 researchers

Srivari Chandrasekhar, senior scientist, Organic Chemistry Division, Indian Institute of Chemical Technology (IICT), has been conferred Fellow of Indian Academy of Sciences, Bangalore.

According to a press release here on Tuesday, Dr. Chandrasekhar has been conferred the honour for his significant contribution in organic chemistry and medicinal chemistry.

The major contributions include synthesis of complex natural products, especially of marine origin with anti-cancer and anti-depressant properties, green chemistry and automation chemistry to make large number of new chemicals.

He has produced 25 Ph.D. students and published more than 200 papers in international journals. He is also a fellow of National Academy of Sciences.

Srivari-ChandrasekharIndia has achieved many prizes in 2014. Before the year ends IICT scientist Srivari Chandrasekhar has added one more prize, he wins Infosys Prize. The scientist who has made important contributions in potential drug developments. Srivari Chandrasekhar from CSIR-IICT , Hyderabad, was announced the winner of the Infosys Prize 2014 in Physical Sciences. The award includes a purse of Rs. 55 lakh, a 22 carat gold medal and citation. The award will be presented by The President on January 5 in Kolkata. The prize is awarded annually by the Infosys Foundation.

He had won the CSIR Technology award-2014 along with his team member

Chandrasekhar’s current contribution is to develop a technology for manufacturing Misoprostal, an abortive drug also used in the treatment of ulcers. Now we can easily get rid of Ulcer.

He has successfully prepared some important drug molecules such as bedaquiline for multi-drug resistant TB, Galantamine for Alzheimer’s disease, Sertraline for treatment of depression, Nebivolol for hypertension and marine natural products such as Eribulin, Azumamide, Arenamide and Bengazole which are scarce to get from nature, with potent biological activities.

As he moves on achieving his target , he has made contributions in synthesizing complex and scarcely available natural products in the laboratory using easily available chemicals.

Chandrasekhar has over 250 publications in national and international journals to his credit.

Prof. Chandrasekhar has displayed an exceptional flair for identifying and synthesizing molecules of biological relevance, topical synthetic interest and utility to industry. His research efforts, with an impressive degree of innovations and enterprise, have led to the synthesis of complex and scarcely available natural products and new molecular entities for affordable healthcare. His endeavors have provided cost-effective technologies to chemical industry through identification of new reagents / solvents for specific transformations. Chandrasekhar’s group has synthesized several classes of complex natural products in optically pure form employing chiral pool precursors and catalytic asymmetric reactions and his syntheses of pladienolide, azumamide, bengazole etc., bear testimony to the efficacy of such approaches.

His passion and commitment to topical health related problems is through provisioning for better and affordable access to important drugs. Mention may be made of hissynthesis of bedaquiline, the first drug approved by FDA after a gap of over 40 years for the treatment of multi-drug resistant TB through simpler transformations and higher yields to ensure ready availability. He along with a team atIICT has developed a scalable synthetic route for misoprostol (a hormone like biologically important synthetic prostaglandin) used to prevent gastric ulcer, induce labor and / or abortion (particularly for safe termination of unwanted pregnancies), which has already been commercialized.

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Grapefruit flavor NOOTKATONE

 Uncategorized  Comments Off on Grapefruit flavor NOOTKATONE
Feb 252015
 

ds.reddy


D. Srinivasa Reddy of CSIR-National Chemical Laboratory Pune devised (J. Org. Chem. 2013, 78, 8149. DOI: 10.1021/jo401033j) a cascade protocol of Diels-Alder cycloaddition of 8 to the diene 7 followed by intramolecular aldol condensation, to give the enone 9. Oxidative manipulation followed by methylenation completed the synthesis of the commercially important grapefruit flavor Nootkatone (10).

Abstract Image
A simple and efficient synthesis of functionalized cis-hydrindanes and cis-decalins was achieved using a sequential Diels–Alder/aldol approach in a highly diastereoselective manner. The scope of this method was tested with a variety of substrates and was successfully applied to the synthesis of two natural products in racemic form. The highlights of the present work provide ready access to 13 new cis-hydrindanes/cis-decalins, a protecting group-free total synthesis of an insect repellent Nootkatone, and the first synthesis of a Noreremophilane using the shortest sequence.

A simple and efficient synthesis of functionalized cis-hydrindanes and cis-decalins was achieved using a sequential Diels–Alder/aldol approach in a highly diastereoselective manner. The scope of this method was tested with a variety of substrates and was successfully applied to the synthesis of two natural products in racemic form. The highlights of the present work provide ready access to 13 new cis-hydrindanes/cis-decalins, a protecting group-free total synthesis of an insect repellent Nootkatone, and the first synthesis of a Noreremophilane using the shortest sequence.

(4R*,4aS*,6R*)-4,4a-Dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaph thaen-2(3H)-one ((±)-Nootkatone 20)

(±)-Nootkatone 20 (19 mg, 65%). IRυmax(film) 2923, 1668, 1606, 1459 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.77 (s, 1 H), 4.74 (s, 1 H), 4.72(s, 1 H), 2.50 (ddt, J = 15.3, 5.0, 1.8 Hz, 1 H), 2.40–2.24 (m, 4 H), 2.04–1.89 (m, 3 H),1.74 (s, 3 H), 1.40–1.29 (m, 2 H), 1.11 (s, 3 H), 0.96 (d, J = 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.9, 170.7, 149.3, 124.8, 109.4, 44.0, 42.2, 40.6, 40.5, 39.5, 33.2, 31.7, 21.0, 17.0, 15.0.

 

 

Nootkatone
Nootkatone.svg
Names
IUPAC name

4-α,5-Dimethyl-1,2,3,4,4α,5,6,7-octahydro-7-keto-3-isopropenylnaphthalene
Other names

(+)-nootkatone
Identifiers
CAS number 4674-50-4 Yes
ChEMBL ChEMBL446299 Yes
ChemSpider 1064812 Yes
Jmol-3D images Image
KEGG C17914 Yes
PubChem 1268142
Properties
C15H22O
Molar mass 218.33 g·mol−1
Appearance Viscous yellow in its liquid form
Density 0.968 g/mL
Melting point 36 °C (97 °F; 309 K)
Boiling point 170 °C (338 °F; 443 K)
Hazards
S-phrases S23 S24 S25
Flash point ~ 100 °C (212 °F)

 

Nootkatone is a natural organic compound and is the most important and expensive aromatic of grapefruit.[1] It is a sesquiterpeneand a ketone.

Nootkatone was previouslythought to be one of the main chemical components of the smell and flavour of grapefruits. In its solid form it is usually found as crystals. As a liquid, it is viscous and yellow. Nootkatone is typically extracted from grapefruit, but can also be manufactured with genetically modified organisms, or through the chemical or biochemical oxidation of valencene. It is also found in Alaska yellow cedar trees[2] and vetiver grass.[3]

 

 

Uses

Nootkatone in spray form has been shown as an effective repellent/insecticide against deer ticks[3][4][5] and lone star ticks.[4][5] It is also an effective repellent/insecticide against mosquitos, and may repel bed bugs, head lice and other insects.[6] It is environmentally friendly insecticide, because it is a volatile essential oil that does not persist in the environment.[6] It is nontoxic to humans, is an approved food additive,[6] and “is commonly used in foods, cosmetics, and pharmaceuticals”.[3]

The CDC has licensed patents to two companies to produce an insecticide and an insect repellant.[6] Allylix, of San Diego, CA, is one of these licensees [7] and has developed an enzyme fermentation process that will produce nookatone more cost effectively.[8]

References

  1.  Furusawa, Mai; Toshihiro Hashimoto; Yoshiaki Noma; Yoshinori Asakawa (November 2005). “Highly Efficient Production of Nootkatone, the Grapefruit Aroma from Valencene, by Biotransformation”. Chem. Pharm. Bull. 53 (11): 1513–1514. doi:10.1248/cpb.53.1513.PMID 16272746.
  2.  Panella, NA.; Dolan, MC.; Karchesy, JJ.; Xiong, Y.; Peralta-Cruz, J.; Khasawneh, M.; Montenieri, JA.; Maupin, GO. (May 2005). “Use of novel compounds for pest control: insecticidal and acaricidal activity of essential oil components from heartwood of Alaska yellow cedar.”. J Med Entomol 42 (3): 352–8. doi:10.1603/0022-2585(2005)042[0352:UONCFP]2.0.CO;2. PMID 15962787.
  3. Jan Suszkiw (January 2011). “Lignin + Nootkatone = Dead Ticks”. USDA.
  4. Dolan, MC.; Jordan, RA.; Schulze, TL.; Schulze, CJ.; Manning, MC.; Ruffolo, D.; Schmidt, JP.; Piesman, J.; Karchesy, JJ. (Dec 2009). “Ability of two natural products, nootkatone and carvacrol, to suppress Ixodes scapularis and Amblyomma americanum (Acari: Ixodidae) in a Lyme disease endemic area of New Jersey”. J Econ Entomol 102 (6): 2316–24. doi:10.1603/029.102.0638. PMID 20069863.
  5.  Jordan, Robert A.; Schulze, Terry L.; Dolan, Marc C. (January 2012). “Efficacy of Plant-Derived and Synthetic Compounds on Clothing as Repellents Against Ixodes scapularis andAmblyomma americanum (Acari: Ixodidae)”. Journal of Medical Entomology 49 (1): 101–106. doi:10.1603/ME10241. PMID 22308777.
  6.  Richard Knox (April 18, 2011). “Repelling Bugs With The Essence Of Grapefruit”. NPR.
  7.  Bigelow, Bruce (2011-04-28). “Nootkatone, So A-peeling in Grapefruit, is Repellent to Mosquitoes and Ticks”. xconomy.com. Retrieved 10 August 2012.
  8. “Cost effective fermentation replaces costly exration”. Allylix. Retrieved 10 August 2012.

External links

Dr. D. Srinivasa Reddy

https://www.linkedin.com/pub/d-srinivasa-reddy-dsreddy/1/75a/139

Research areas

  • Total Synthesis
  • Medicinal Chemistry

Our group research interests are broadly in total synthesis of biologically active compounds and medicinal chemistry. Current projects include the total synthesis of bioactive natural products such as antiinflammatory agents, antibacterial agents, antimalarial compounds and anti-cancer agents. Targets are chosen for their interesting biological activity and moderate complexity, which drives our creative solutions to their synthesis. Our ability to achieve an efficient synthesis enables us to access sufficient quantities of target molecule for biological profiling and ready access to different analogs that may prove to be more selective and efficacious as a drug-like molecule. We have plans to divert our total synthesis projects into medicinal chemistry projects by simplifying the complex structures. In medicinal chemistry front, our main interest is to use “silicon-switch approach” to discover novel drugs or drug-like molecules with improved pharmacokintetic (PK) and pharmacodynamic (PD) properties.

s reddy ncl

DEC2014 NCL PUNE INDIA

DR ANTHONY WITH DR REDDY

Contact

  • Dr. D. Srinivasa Reddy
    Senior Scientist
    Office: R.No-282, Main building
    Organic Chemistry Division
    National Chemical Laboratory
    Dr. Homi Bhabha Road
    Pune 411008, India
    Phone  +91 20 2590 2445
    Fax +91 20 2590 2624
    E-mail ds.reddy@ncl.res.in 

 

 

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