UFRGS- Universidade Federal do Rio Grande do Sul Faculdade de Farmcia Programa de Ps-Graduao em Cincias farmacuticas

Semi sntese de anlogos de curcumina Rose Bandeira Gari Ccana

Fig. 1. The role of genes and environment in the development of cancer

Anand et al., Pharm Res. 2008; 25(9): 20972116.

Fig. 2. Genes associated with risk of different cancers.

Anand et al., Pharm Res. 2008; 25(9): 20972116.

Fig. 3. Cancers that have been linked to alcohol and smoking.

Alcohol NF-B proinflammatory tumorigenesis

Tobaco NF-B inflammation Cancer Anand et al., Pharm Res. 2008; 25(9): 20972116.

2530% of all deaths from cancer 87% of deaths from lung cancer

Fig. 4. Cancer deaths (%) linked to diet as reported by Willett.

In 1981, Doll and Peto estimated that approximately 30 35% of cancer deaths in the USA were linked to diet.

Most carcinogens that are ingested, such as nitrates, nitrosamines, pesticides, and dioxins, come from food or food additives or from cooking. Anand et al., Pharm Res. 2008; 25(9): 20972116.

Fig. 5. Various cancers that have been linked to obesity.

Obesity hyperglycemia Adipocytes: leptin, TNF, IL-1 NF-B, carcinogenesis

Anand et al., Pharm Res. 2008; 25(9): 20972116.

Fig. 6. Various cancers that have been linked to infection.

All viruses linked to cancer have been shown to activate the inflammatory marker, NF-B.

Worldwide, an estimated 17.8 % of neoplasms are associated with infections; less than 10% in highincome countries to 25% in African countries.

Anand et al., Pharm Res. 2008; 25(9): 20972116.

Fig. 7. Various cancers that have been linked to environmental carcinogens.

Anand et al., Pharm Res. 2008; 25(9): 20972116.

Fig. 8. Relationship between production of spices and cancer incidence.

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas Aggarwal et al., Exp Biol Med 2009, 234:825-849.

Fig. 9. Fruits and vegetables with potential to prevent cancer.

Anand et al., Pharm Res. 2008; 25(9): 20972116.

Fig. 10. Spices, condiments and cereals with potential to prevent cancer.
+ 25000 Phytochemicals

Anand et al., Pharm Res. 2008; 25(9): 20972116.

Gupta et al., Cancer Metastasis Rev (2010) 29:405434

Curcuma longa

Goel et al., Mol. Nutr. Food Res. 2008, 52, 1010

Curcumin

Goel et al., Mol. Nutr. Food Res. 2008, 52, 1010

Kunnumakkara et al., Cancer Lett 269 (2008) 199225

 effectiveness against various types of cancer : chemopreventive and chemotherapeutic propertie Unlike most chemotherapeutic agents, curcumin is reported to show little to no toxicity (no dose-limiting toxicity at doses up to 10 g/day in humans). Unfortunately, the potential utility of curcumin is somewhat limited due to poor bioavailability and poor selectivity. The lack of selectivity is due to the numerous molecular targets with which curcumin is known to interact.

The ketoenol tautomerization and functional regions of curcumin.

Heptadiendione analogues of curcumin:

pentadienone analogues of curcumin:

Syntheses of compounds 14, 6 and 10

Pabon, H. Y. Y. (1964) A synthesis of curcumin and related compounds. Recueil des Travaux Chimiques des Pays-Bas . 83; 4, 379-386.

Boron oxide + acetylacetone ---+ 3,4-dimethoxybenzaldehyde + tributylborate

Synthesis of compounds 12 and 13

Heller and Natarajan. Org Lett. 2006 , 22;8(13):2675-8.

Synthesis of compounds 1419, 23 and 24

Synthesis of sulfamoylated curcumin analogues 5, 8, 9, 11, 2022

The application of N,N-dimethylacetamide as solvent clearly accelerated the sulfamoylation reaction of a hydroxyl group compared with the solvents used so far. The target sulfamates were obtained in the highest yield without a base.
Okada et al., Tetrahedron Letters 41 (2000) 7047-7051

Anti-proliferative activities of selected curcumin analogues on cancer and normal cells

 Sntese de > 50 novos anlogos de 1,5-bis(4-hidroxi-3-metoxifenil)-penta-(1E, 4E)-1,4dien-3-one (C5-curcumina) e e avaliao de sua citotoxicidade frente a clulas de cncer de colon (HCT-116);

Anlogo natural isolado dos rizomas de Curcuma domestica

Sntese dos 1,5- diaril-3-oxo-1,4-pentadienos: condensao aldlica

SAR preliminar de C5 curcumina

C5 curcumina

SAR de C5- versus C7-curcuminides

3-oxo-1,4-pentadieno Indispensvel na funo de induo de citotoxicidade

SAR de anis aromticos (efeito dos substituintes)

Avaliao de substituies (metoxilas ) no grupo aril: Citotoxicidade aumentou com o nmero de substituintes metoxila
Grupo orto-metoxil: diminuio citotoxicidade

SAR de anlogos tetra e hexasubstitudos Substituies nas posies meta e para

 Introduo de vrios grupos funcionais na posio para manteve atividade citotxica (exceto para GO-Y082)

SAR de C5 curcuminides

Desenvolvimento de molculas : substituies na posiso para

Quase todos os compostos exibiram alta inibio do crescimento celular;

Curcuma longa

OBRIGARO!

Goel et al., Mol. Nutr. Food Res. 2008, 52, 1010

The Aldol Condensation

Addition of ammonia derivatives

ketones react with primary amines to form a class of compounds called imines.

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