A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence

Abstract

(−)-Deguelin is a rotenoid natural product that possesses significant potential as a chemopreventive and chemotherapeutic agent. While several racemic syntheses of deguelin have been reported, a formal evaluation of the anticancer activity of both the natural and unnatural enantiomers remains lacking. We describe herein the successful application of a flexible and selective thiourea-catalyzed cyclization strategy toward the enantioselective total synthesis of deguelin, which allows access to either stereoisomer for biological studies. The synthesis was completed in six steps (longest linear) with no protecting groups. The evaluation of both enantiomers of the natural product demonstrated potent inhibition of several cancer cell lines by these compounds, but interestingly showed that the unnatural (+)-deguelin preferentially inhibited the growth of MCF-7 breast cancer and HepG2 liver carcinoma cells when compared to the natural product.

Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain

“…For example, resins that contain rotenoids extracted from the roots of Lonchocarpus utiliz (cubé), Lonchocarpus urucu (barbasco), Derris elliptica (tuba plant), or Derris involuta (jewel vine) have been used in many countries as natural insecticides, acaricides, and/or piscicides (11,12). Deguelin also has therapeutic effects against a range of cancers-for example, in lung, stomach, and prostate-being able to inhibit tumor progression (13)(14)(15)(16)(17)(18)(19) with potent apoptotic and antiangiogenic activities in vitro (20).Deguelinisalsousedtoimprovethesuccessoforgan transplantation by reducing associated inflammation (21).A l t h o u g ht h e r ew e r es o m ee a r l yc o n c e r n sa b o u tt h e safety of using deguelin in mammals as a result of the lethal effect of the analog rotenone on fishes and arthropods (13,14), and because of Parkinson'sd i s e a s e -like symptoms in mice after chronic administration of deguelin (6 mg/kg/d) (22), no appreciable levels of toxicity or adverse effects of deguelin at therapeutic doses (2-5mg/kg) have been recorded in rodents (mice and rats) (15,17,23,24). Deguelin has been reported to exert its effects on rapidly replicating cells.…”

“…For example, resins that contain rotenoids extracted from the roots of Lonchocarpus utiliz (cubé), Lonchocarpus urucu (barbasco), Derris elliptica (tuba plant), or Derris involuta (jewel vine) have been used in many countries as natural insecticides, acaricides, and/or piscicides (11,12). Deguelin also has therapeutic effects against a range of cancers-for example, in lung, stomach, and prostate-being able to inhibit tumor progression (13)(14)(15)(16)(17)(18)(19) with potent apoptotic and antiangiogenic activities in vitro (20).Deguelinisalsousedtoimprovethesuccessoforgan transplantation by reducing associated inflammation (21).…”

Natural product-inspired rational design, synthesis and biological evaluation of 2,3-dihydropyrano[2,3- f ]chromen-4(8 H )-one based hybrids as potential mitochondrial apoptosis inducers

“…All the synthesized pyranochromanone based hybrid molecules 15aef, 20aeb, 21 and 22 were screened for in vitro cytotoxic activities against three different human cancer cell lines namely breast cancer cell line (MCF-7), lung carcinoma cell line (A549) and cervical cancer cell line (HeLa) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method while (À)-deguelin [20] and anti-cancer drug levamisole [49] were taken as the reference. The results are summarized in Table 1.…”

“…(À)-Deguelin (i, Fig. 1) is a natural product [19,20] possessing pyranochromanone moiety in its basic scaffold exhibits cytotoxicity against a wide range of human cancer cell lines including . However, potential side effects of deguelin over certain dose is a substantial obstacle to its clinical use [24].…”

Synthesis of some novel pyrano[2,3-f]chromenone derivatives

“…1) was originally isolated from African plant Mundulea sericea and has depicted strong anticancer activity in various in vitro and in vivo studies for a number of cancers [9][10][11] including prostate [12], lung [13,14], and breast [15,16]. It is believed that it induces apoptosis in premalignant and malignant human bronchial epithelial (HBE) cells with no effect on the growth of normal HBE cells.…”