SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME

NOVEL STILBENEANALOGUES

PROTOCOL FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

BY

G.N.V.SUNIL KUMAR,B.Pharm.,

Department of Pharmaceutical Chemistry,

2008-2009

UNDER THE GUIDENCE OF

N.K.SATHISH., M.Pharm.,

ASSISTANT PROFESSOR

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

BHARATHICOLLEGE OF PHARMACY

BHARATHI NAGARA, MANDYA

KARNATAKA -571422.

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the Candidate and Address (In Block Letters) / PRESENT ADDRESS
G.N.V.SUNIL KUMAR,
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY,
C/O BHARATHICOLLEGE OF PHARMACY,
BHARATHI NAGARA,
MANDYA (DIST),KARNATAKA-571422.
2. / Name of the Institution / BHARATHICOLLEGE OF PHARMACY,
BHARATHI NAGARA, MANDYA.-571422.
3. / Course of Study and Subject / MASTER OF PHARMACY IN PHARMACEUTICAL CHEMISTRY.
4. / Date of Admission of Course / 30-06-2008
5. / Title of Topic / SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL STILBENE ANALOGUES
6. / Brief Resume of the Intended Work
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study / ENCLOSURE-I
7 /

Materials and Methods

7.1 Source of data

7.2 Method of collection of data

7.3 Does study require any investigations or interventions to conducted on patients or other human or animal? If so, please describe briefly.

7.4 Has ethical clearance been obtained from your institution in case of 7.3

/ ENCLOSURE-II
8 / List of References / ENCLOSURE-III
9.

10.

11.


12. /
Signature of the candidate:
(G.N.V. Sunil Kumar)
Remarks of the guide: This work can be carry out in our laboratory
Name And Designation of:
Sathish.N.K., M.Pharm.,
11.1 Guide Assistant Professor,
Department of Pharmaceutical Chemistry,
BharathiCollege of Pharmacy,
Bharatinagara,Mandya(dist),
Karnataka-574122.
11.2 Signature
11.3 Co-Guide -----
11.4 Signature

11.5 Head of the department Dr. Senthil Kumar.G.P.,M.Pharm.,Ph.D.,
Professorand Head of Department
Pharmaceutical Chemistry,
BharathiCollege of Pharmacy,
Bharathinagara, Mandya(Dist),
11.6 Signature Karnataka-574122.
12.1 Remarks of the Chairman and Principal:
FORWARDED FOR APPROVAL Dr. Tamizh Mani .T
Principal
BharathiCollege of Pharmacy,
Bharathinagara,Mandya (Dist),
Karnataka-571422.
12.2Signature

ENCLOSURE-I

6. BRIEF RESUME OF INTENDE WORK

6.1 NEED FOR STUDY

Cancer is a deadly disease causing significant morbidity and mortality. Current existing cancer therapeutic agents provide only marginal benefit for treatment of some cancers. Thus, the development of novel agents for cancer therapy is of great interest.

Stilbenes are a group of natural compounds with a wide range of biological activities. The present invention is directed to stilbene derived compounds having antineoplastic activity.The present invention is directed to certain new stilbene derivatives having antineoplastic activity against cancerous cell lines.

Stilbene derivatives exhibit killing and suppression of growth activity against a variety of cancer cells, and are effective at suppressing tumor growth in vivo. The stilbene derivatives may be used in the treatment of diseases characterized by cell hyperproliferation including human malignancies and non-malignant diseases such as liver cirrhosis. Stilbenes may also disrupt abnormal vessels in tumor to achieve vascular disrupting effect to suppress tumor growth. Water soluble pro-drug forms of stilbene derivatives are particularly useful in suppressing tumor growth in vivo.

A stilbene derivative of the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof have low toxicity, but are water soluble and effective as carcinostatics.

6.2 REVIEW OF LITERATURE

Lewet al., prepared phenyl stilbene derivatives using the safety catch linker [01].

Majimaet al., reported Isomerization, Oxidation, and Dimerization of Radical Cations of Stilbene Derivatives [02].

Baderschneideret al., reported Isolation and characterization of novel stilbene derivatives from Riesling wine. [03].

Hirohitoet al., synthesized stilbene derivatives by introduced dialkylamino and trimethylammonio groups for second-order nonlinear optics [04].

Medina.etal., synthesized and reported Biological Properties of New Stilbene Derivatives of Resveratrol as New Selective Aryl Hydrocarbon Modulators [05].

Chusmanet al.,reported Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization [06].

Yue-quig li et al., reported Synthesis ofstilbene derivatives with inhibition ofSARS coronavirus replication [07].

Jeffery et al., reported One-pot palladium-catalyzed highly chemo-, regio-, and stereo selective synthesis of trans-stilbene derivatives. A concise and convenient synthesis of resveratrol [08].

Yanget al., reported synthesis and cytotoxicity of new trans-Stilbene benzene sulfonamide derivatives [09].

Robertiet al., reported Synthesis and Biological Evaluation of Resveratrol and Analogues as Apoptosis-Inducing Agents [10].

Kimet al., reported Design, Synthesis, and Discovery of Novel trans-Stilbene Analogues as Potent and Selective Human Cytochrome P450 1B1 Inhibitors [11].

6.3 OBJECTIVE OF STUDY

  1. The main objective of the study is to synthesizenovel stilbene analogues.
  2. The synthesized stilbene derivatives will be characterized by using IR, NMRMASS spectroscopic techniques.
  3. To evaluate the biological activity of synthesized stilbene analogues.

ENCLOSURE –II

7.MATERIAL AND METHOD:

7.1 SOURCE OF THE DATA

The literature survey on the area on present investigation will be done by referring chemical abstracts of all the national and international journals pertaining to synthetic, medicinal and pharmaceutical chemistry.

The information about pharmacological and biological activities will be collected by referring European journals of Medicinal chemistry, current Medicinal chemistry, Bio-organic Medicinal chemistry etc.

For this purpose the library facilities are available at our college, Indian Institute of science Bangalore & IICT,Hyderabad will be made use of. The day-to-day development in this area will be updated by literature survey through E-publishing & current periodicals in our library & elsewhere.

All the basic facilities required for synthetic pharmaceutical chemistry are available in our college laboratories. For purification of the products TLC, column chromatography, HPLC & other facilities such as vacuum pump, rotary vacuum evaporators are also available in our laboratory.

7.2 METHOD OF COLLECTION OF DATA:

The chemical structure of the synthesized compounds shall be established on the basis of physical, chemical and analytical data. Melting point of new compounds shall be determined in open capillary tube. They are expressed in degree Celsius.

The compound synthesized will be characterized by UV,IR, NMR ,C13NMR & mass spectral data. This will be collected by sending the sample to other advanced research centers like IISC,Bangalore, IICT, Hyderabad & IIT, Chennai.

All the molecules will be screened for their biological activity in our laboratory.

7.3 Does the study require any investigation or interventions to beconductedon

Patients or other humans or animals?

Yes

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

Yes, attached ethical clearance certificate.

ENCLOSURE-III

8. REFERENCES:

  1. Amy LewA.,Richard Chamberlin. “The Preparation of Phenyl-stilbene Derivatives Using the Safety Catch Linker”’ Methods in Molecular Biology,2002, 201, 93-109.
  2. Tetsuro Majima, Sachiko Tojo, Akito Ishida, Setsuo Takamuku. “Reactivities of Isomerization, Oxidation, and Dimerization of Radical Cations of Stilbene Derivatives”, Journal of physical chemistry,1996, 100 (32), 13615–13623.
  3. Baderschneider B.,Winter Halter P. “Isolation and characterization of novel stilbene derivatives from Riesling wine”. Journal of agricultural food chemistry,2000,48(7),2681-2686.
  4. UmezawaHirohito., Suzuki Masumiokada., & Shuji Nakanishi Hachiro., “Synthesis of stilbene derivatives introduced dialkylamino and trimethylammonio groups for second-order nonlinear optics”. Nippon Kagakkai Koen Yokoshu, 2006, 86,702.
  5. Philippe de Medina., Robert Casper., Jean-François Savouret., & Marc Poirot., “Synthesis and Biological Properties of New Stilbene Derivatives of Resveratrol as New Selective Aryl Hydrocarbon Modulators”. Journal of Medicinal Chemistry,2005, 48,287–291.
  6. Cushman., Nagarathnam M.,Gopal D., Chakraborti D., Lin A.K ., & Hamel C.M. “Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization”. Journal of Medicinal Chemistry, 1991, 47, 2579-2588.
  7. Yue-Qing Li., Ze-Lin Li., Wei-Jie Zhao., ui-Xing Wen., Qing-Wei Meng.,& Yi Zeng.“Synthesis ofstilbene derivatives with inhibition ofSARS coronavirus replication”. European Journal of Medicinal Chemistry, 2006, 41, 1084-1089.
  8. Tuyet Jeffery.,Benoı̂t Ferber.,“One-pot palladium-catalyzed highly chemo-, regio-, and stereo selective synthesis of trans-stilbene derivatives. A concise and convenient synthesis of resveratrol”. Tetrahedron letters, 2003, 44, 193-197.
  9. Li-Ming Yang., Shwu-JiuanLin., Fen-Lin Hsu Tsang-Hsiung Yang., “Antitumor agents. Part 3: synthesis and cytotoxicity of new trans-Stilbene benzene sulfonamide derivatives”. Bioorganic & medicinal chemistry, 2002,12, 1013-1015.
  10. Marinella Roberti., Daniela Pizzirani., Daniele Simoni., Riccardo Rondanin., Riccardo Baruchello., Caterina Bonora., Filippo Become., Stefania Grimaudo, Manlio Tolomeo. “Synthesis and Biological Evaluation of Resveratrol and Analogues as Apoptosis-Inducing Agents”. Journal of medicinal chemistry, 2003, 46(16), 3546–3554.
  11. Sanghee Kim., Hyojin Ko., JaeDun Park., Sungkyu Jung., Sang Kwang Lee., &Young-Jin Chun. “Design, Synthesis, and Discovery of Novel trans-Stilbene Analogues as Potent and Selective Human Cytochrome P-450 1B1 Inhibitors”.Journal of medicinal chemistry,2002, 45 (1), 160–164.