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SYNTHESIS AND EVALUATION OF NOVEL CHROMONE BASED EPOXIDES AS ANTI- CANCER AGENTS

Simer Mann M. Pharmacy Third Semester

WHAT IS CANCER?

Cancer is a class of diseases characterized by abnormal cell division Excessive cell division leads to formation of lumps or masses of tissue called tumors Cancer spreads via blood stream or lymphatic system United States data 2012 New cases: 1,638,910 Deaths: 577,190

WHAT CAUSES CANCER?


Genes

- the DNA type: Oncogenes Tumor suppressor genes Suicide genes DNA repair genes Carcinogens Genetic factors Other Medical factors

CLASSIFICATION OF CANCER
Carcinoma Sarcoma
skin or in tissues that line or cover internal organs

in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.

Adenomas
Lymphoma Leukemias

in the thyroid, the pituitary gland, the adrenal gland begin in the lymph nodes and immune system tissues.

in blood-forming tissue such as the bone marrow

5 MAJOR STEPS IN METASTASIS


1. 2.

3. 4. 5.

Invasion and infiltration of surrounding normal host tissue with penetration of small lymphatic or vascular channels; Release of neoplastic cells, either or single cells or small clumps, into the circulation; Survival in the circulation; Arrest in the capillary beds of distant organs; Penetration of the lymphatic or blood vessel walls followed by growth of the disseminated tumor cells

Targets of Anti-Cancer Agents


Insulin-like growth factor receptor inhibitors- e.g. Genestein and Cyclolignan
Angiogenesis inhibitors-e.g. Endostatin,Vasostatin Vascular Endothelial Growth Factor inhibitors (VEGF)- e.g. Sunitinib, Orafenib Epidermal Growth Factor Receptor (EGFR) inhibitors- e.g. Gefitinib, Erlotinib Aurora kinases- e.g. Tozasertib Peroxisome proliferator activated receptor- (PPAR) inhibitors-e.g. Biperdin Matrix Metalloproteinase inhibitors-e.g. Marimastat, Cipemastat Farnesyl transferase inhibitors-e.g. Lonarfenib

Heat shock proteins- e.g. Geldanamycin


Cyclin dependent kinase inhibitors-e.g. Roscovitine

Chromones as Anti-cancer Agents


OH
O

O Cl

OH

O OH
HO
O

O OH N CH3

O OH

COOH

1 Burgers medicinal drug discovery 1999 5th ed, 1,

2 Bioorg.Med. Chem. 2000, 8, 239

3 Tetrahedron Lett. 2001 42, 1631

OCH3 O HO H F O HO CH3 F H O N O 6 H

O OH

O H O 4 5
J. Antibiot. 2006, 59, 86.

H O N O

Contd.

N O O O NH2

O S O
7

Me HO O CF3 N O
Chemistry of heterocyclic compounds. 2005, 41(3), 354
8

O Br

Het

9
Annu. Rev. Immunol. 1998, 16, 395.

Bioorg . Med. Chem. 2007, 15, 5191

OH OH O O N O N OH O O O O O NH H3CO N O O O

10

11

12

13

British Journal of Cancer. 2005, 93, 1011.

OBJECTIVE
Synthesis of novel (final derr.) Characterization via 1H NMR, 13C NMR, IR ,Mass Spectroscopy's and Elemental analysis Cytotoxic Evaluation of synthesized compounds

Establishment of structure activity relationship

Schematic Work Representation


STEP-1 Synthesis of subsituted o-Hydroxyacetophenones
OH X
1

OCOCH3 X CH3COCl
1

OH Anhydrous AlCl3 X
1

COCH3

X2 X
3

X2 X
3

Fries Rearrangement

X2 X3
23

21

22

a. X1 = H, X2 = H, X3 = H b. X1 = H, X2 = H, X3= Cl c. X1= H, X2= Cl, X3 = H d. X1 = Cl, X2 = H, X3 = H e. X1 = H, X2 = H, X3 = Br f. X1 = H, X2 = Br, X3 = H g. X1 = H, X2 = H, X3= CH3 h. X1 = H, X2 = H, X3 = F i . X1 = H, X2 = F, X3= H j. X1 = H, X2 = Cl, X3 = F

Scheme 1

STEP-2 Synthesis of subsituted 3-formylchromones

OH X1 X2 X3
24

O COCH3 X3

O H

DMF, POCl3
X2 X1
25

VilsmeierHaack reaction

a. X1 = H, X2 = H, X3 = H b. X1 = H, X2 = H, X3= Cl c. X1= H, X2= Cl, X3 = H d. X1 = Cl, X2 = H, X3 = H e. X1 = H, X2 = H, X3 = Br f. X1 = H, X2 = Br, X3 = H g. X1 = H, X2 = H, X3= CH3 h. X1 = H, X2 = H, X3 = F i . X1 = H, X2 = F, X3= H j. X1 = H, X2 = Cl, X3 = F

Scheme-2

STEP 3- Synthesis of Allylated derivatives


O X3 X
2

O H

O X1 25

Br

K2CO3 / Acetone Reflux

X3 X2 X1 26 O

a. X1 = H, X2 = H, X3 = H b. X1 = H, X2 = H, X3= Cl c. X1= H, X2= Cl, X3 = H d. X1 = Cl, X2 = H, X3 = H e. X1 = H, X2 = H, X3 = Br f. X1 = H, X2 = Br, X3 = H g. X1 = H, X2 = H, X3= CH3 h. X1 = H, X2 = H, X3 = F i . X1 = H, X2 = F, X3= H j. X1 = H, X2 = Cl, X3 = F

Step 4. Synthesis of Chromone based Epoxides


O X3 aq. NaOCl X2 X
1

O X3

O 26

X2 X1

O 27

a. X1 = H, X2 = H, X3 = H b. X1 = H, X2 = H, X3= Cl c. X1= H, X2= Cl, X3 = H d. X1 = Cl, X2 = H, X3 = H e. X1 = H, X2 = H, X3 = Br f. X1 = H, X2 = Br, X3 = H g. X1 = H, X2 = H, X3= CH3 h. X1 = H, X2 = H, X3 = F i . X1 = H, X2 = F, X3= H j. X1 = H, X2 = Cl, X3 = F

Work Done
S.No Chromones Compound No. X1 1. 2. 3. H H H X2 H H Cl X3 H Cl H 26a 26b 26c 10 11 11 72 72 72 Reaction Time (hrs) Yield products (%) of

4.
5. 6.

Cl
H H

H
H Br

H
Br H

26d
26e 26f

11
12 12

73
73 74

7.
8. 9. 10.

H
H H H

H
H F Cl

CH3
F H F

26g
26h 26i 26j

13
12 12 11

76
78 71 69

Work to be Done
S.No Chromones Compound No. X1 11. 12. 13. H H H X2 H H Cl X3 H Cl H 27a 27b 27c Reaction Time (hrs) Yield products (%) of

14.
15. 16.

Cl
H H

H
H Br

H
Br H

27d
27e 27f

17.
18. 19. 20.

H
H H H

H
H F Cl

CH3
F H F

27g
27h 27i 27j

On this cartoon I would explain that cancer is a terrorist cell.. . Lol