Challenges in establishing potent cancer chemotherapy using newly synthesized 1,5-Diaryl-3-Oxo-1,4-Pentadiene analogs of curcumin

Curcumin is a dietary pigment that imparts yellow color to turmeric. It has been used as a traditional medicine, mainly in the South Asian countries. Very recently, curcumin has been revealed to reregulate overexpression of cancer-related molecules, such as NF- ?B signaling molecules, molecules controlling tumor cell growth, cell cycle regulators, anti-apoptotic molecules, and molecules associated with invasion, metastasis, and angiogenesis, primarily by their degradation. Low toxicity of curcumin has a potential advantage, particularly in combination with other cytotoxic agents. Multitargeted potential of this compound can overcome problems concerning redundancy of cancer biology. However, the achievements made in clinical studies of curcumin have not been successful and promising. Considering these points, I attempted to improve the potency of curcumin. My approach was to develop 1,5-diaryl-3-oxo-1,4-pentadiene (DOP) analogs of curcumin that possess enhanced potency to control and kill cancer cells at much lower concentrations. This strategy has been implemented since the discovery of GO-035, one of the DOP analogs of curcumin, in the newly synthesized organic compound library of Tohoku University, Department of Organic Chemistry. This compound bears 4 times stronger growth suppressive potential than curcumin. Since then, we began to develop and screen DOP analogs of curcumin. In total, 86 species of DOP analogs have been synthesized as leads. Among them, analogs named GO-Y030 and GOY078 have the most enhanced potency to suppress tumor cell growth in a cell panel composed of 16 types of cancer cells. The most enhanced growth suppressive potency of these analogs reached to >80 times higher than that of curcumin. The growth suppressive potency has been exerted through molecular reregulation including c-Myc, KRAS, cyclin D1, ErbB2, β-catenin, COX-2, NF-κB, IRF-4, BLIMP1, CDK6, IL-6, survivin, Bcl-2, Bcl-XL, Notch1, Notch3, STAT3, and AKT. They also exhibit at least 10 times higher apoptosis induction than curcumin. They can induce apoptosis-related molecules including caspases, PARP, TP53, XIAP, and DR5 toward proapoptosis more efficiently than curcumin. They also exhibit improved potential of angiogenesis inhibition and antiinvasion. One of the reasons for poor bioavailability of curcumin is believed to be its hydrophobicity. Among the new leads, the solubility of GO-Y078 is 2 times higher than that of curcumin, and the solubility of GO-Y038 has been predicted to be approximately 20 times higher than that of curcumin. Enhancement of antitumor ability, enhancement of solubility, or both could improve in vivo efficiency. In fact, using GO-Y030 or GO-Y078, in vivo efficacies have been confirmed in mouse models of familial adenomatous polyposis and cancerous ascites of gastric malignancy as well as in colonic cancer stem tumors implanted in mice. These results encourage the development of new cancer treatment protocols using newly synthesized DOP analogs. GO-Y038 also has an increased antitrypanosomal activity.