Abstract
Previously, we synthesized curcumin and a succinate ester prodrug of curcumin namely curcumin diethyl disuccinate (CurDD) in the lab scale, which yielded hundred milligrams to few grams of the compounds. CurDD was found to be more stable in a phosphate buffer pH 7.4 and exhibited better cytotoxicity against Caco-2 cells than curcumin. Here, the one-pot syntheses of curcumin and CurDD were scaled up to afford multigram quantities of both compounds for preclinical studies using a 10-L chemical reactor. The key steps for the synthesis of curcumin were the formation of boron-acetylacetone complex and the decomplexation of boron-curcumin complex. The synthesis of CurDD could be achieved via a one-step esterification between curcumin and succinic acid monoethyl ester chloride using 4-(N,N-dimethylamino)pyridine as a catalyst. The synthesized curcumin and CurDD were then investigated and compared for an anti-tumor activity in HepG2-xenograft mice. CurDD could reduce the tumor growth in HepG2-xenograft mice better than curcumin. CurDD also exerted the stronger inhibition on VEGF secretion, COX-2 and Bcl-2 expression and induced higher Bax expression in comparison with curcumin. The results suggest that CurDD is a promising prodrug of curcumin and has a potential to be further developed as a therapeutic agent or an adjuvant for the treatment of hepatocellular carcinoma.
Highlights
Curcumin (Figure 1A) is a polyphenolic substance found in turmeric (Curcuma longa L.) with numerous pharmacological activities including anti-inflammation [1,2], anti-oxidation [3] and anti-angiogenesis [4]
As shown in Scheme 1, the first step in the synthesis of curcumin is the formation of the boron-acetylacetone complex
The boron-curcumin complex was dissociated by hydrochloric acid (HCl)
Summary
Curcumin (Figure 1A) is a polyphenolic substance found in turmeric (Curcuma longa L.) with numerous pharmacological activities including anti-inflammation [1,2], anti-oxidation [3] and anti-angiogenesis [4]. It has been investigated for anti-cancer activity against several cancer types such as breast, prostate, lung, colon and liver cancers [5]. EEvveenn tthhoouugghh ccuurrccuummiinn hhaass pprroommiissiinnggaannttii--ccaanncceerreefffefcetcst,st,hteheusuesoefocfucrucurcmuimn iinn icnanccaenrccehrecmheomthoetrhaperyaipsyhiisndheinredderbeydthbeypthooerpooroarl boiroaal vbaioilaavbailiiltaybdiluitey tdoutehetocthheemcihceaml inicsatlaibnislittaybailnitdyeaxntdenesxivteenfisirvset-pfiarssts-pmaestsamboeltiasmbo[li1s0m]. PPrrooddrruugg ddeessiiggnn hhaass bbeeeenn uuttiilliizzeedd ttoo iimmpprroovvee uunnddeessiirreedd pphhyyssiiccoocchheemmiiccaall,, bbiioopphhaarrmmaacceeuuttiiccaall aanndd pphhaarrmmaaccookkiinneettiicc pprrooppeerrttiieess ooff sseevveerraallddrruuggssaannddpphhyytotocchheemmicicaalsl.s.PrPerveivoiuosulysl,yw, we ededveevleolpoepdeda asuscuccincainteateesteesrteprrpodrordurguogfocfucrucurcmuimn innanmaemlyelcyurccuurmcuimn idniedthieythl ydlisduicscuicncaitnea(tCe u(CrDuDrD, DFi,gFuirgeu1reB)1Bto) timo ipmropvreovcheecmheicmalicsatal bsitlaibtyilaitnydarneddurecde upcheaspehIaIsme eIItamboeltiasbmoloisfmcuorcfucmuricnu. TThheerreeffoorree,, CCuurrDDDD iiss aa ppootteennttiiaall ccuurrccuummiinn pprrooddrruugg tthhaatt ccaann bbee ffuurrtthheerr ddeevveellooppeedd ffoorr cclliinniiccaall aapppplliiccaattiioonnss
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