| Curcumol is a representative index component for the quality control of the essential oil of Curcuma wenyujinY.H.Chen et C.Ling,which is currently used as an anticancer and antivirus treatment,and is included in the State Pharmacopoeia Commission of the People’s Republic of China(2005).Curcumol is the major bioactive component of the essential oil of Curcuma wenyujin with the structure of a guaiane-type sesquiterpenoid hemiketal.It has present many important bioactivities,such as antitumor,anti-reproduction,anti-inflammatory,antioxidant and so on.Even if clinical used for the treatment of Cervical Cancer through local injection in the 1970s,curcumol can not been developed as a drug for its weak activity and poor pharmacokinetic properties.The chemical structural modification on curcumol is an effective method to deal with these questions.In our work,various derivatives of curcumol have been synthesized and purified to screen and find more powerful compound.The first part of our works is to extract enough curcumol for chemical modification.Curcumol is separated from the essential oil of Curcuma wenyujin for providing raw materials.We found a more abundant resource to collect curcumol conveniently.The residue essential oil of Curcuma wenyujin that has been extracted another component(3-elemene,contain with higher concertration curcumol.It is an economical method extracted from the residue more than from the essential oil of Curcuma wenyujin directly.The second part of our works is involved the chemical modification of curcumol.On the base of the structural features,thirty-four derivatives of curcumol include Ⅰ(C1-C6)、Ⅱ(GE1～GE10,GZ1～GZ6,GA1～GA5)、Ⅲ(CN1～CN4)and some intermediates(G1,E1～E3)were designed and synthesized.Additionally,a new method to separate the chiral isomers(10R)-10,14-epoxycurcumol(E1)and(10S)-10,14-epoxycurcumol(E2)making use of the non-chiral ionic liquid[BMIM]BF4 was founded accidently.The last part of our works focused the bioactivities of these curcumol derivatives.And the preliminary evaluation of these derivatives in vitro anti-tumor activity is screened using an MTT assay with H460 and SGC-7901.Distinct structure activity relationships of these curcumol derivatives were also revealed for inhibiting cell proliferation.The structural modification of 6-hydroxy and the decomposition of hemiacetal’s bridge of curcumol greatly weakened the inhibitory activities of tumor cells in vitro.Presence of electron withdrawing groups or amino in the side chain of C12 position could increase activity significantly.Using Fluo-3 as the Ca2+ indicator,curcumol can cause cytosolic calcium levels to increase in H460 cells but not induce apoptosis.To deepen understanding the anti-tumor mechanism of curcumol,we try to find out the relation between the regulation of intracellular calcium concentration and anti-tumor activity.Nifedipine,a calcium channel blocker,could significantly suppress the inhibitory activities of SGC-7901 cells in vitro.And the anti-tumors effect of rotenone on H460 cell lines could be strengthen remarkable by curcumol within low concentration.For researching the relation between the regulation of intracellular calcium concentration and anti-reproduction activity,the influence of curcumol acting on human sperm motility in vitro was observed.Curcumol and the derivative GE10 could improve the average path velocity(VAP),amplitude oflateral head displacement(ALH)and wobble(WOB)remarkable,while showing their anti-reproduction action through the addition of human sperm malformation rate.Finally,some derivatives with better anti-tumor activity than curcumol were gained through chemical modification.The structure activity relationships of curcumol derivatives were summarized.To study the anti-tumor mechanism preliminary,more characters of action about curcumol were learned.Varies activities of curcumol like as antitumor,anti-reproduction,anti-inflammatory,may be relate to its calcium regulation.Our works should be guide to find new curcumol derivatives for clinical application. |
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