Abstract
With limited success achieved in bladder cancer patient management, novel agents are in urgent need for the purpose of therapy and prevention. As a sesquiterpenoid dimmer isolated from Gochnatia pomculat, (−)-gochnatiolide B has been bio-mimetically synthesized in multiple steps with a poor yield, which heavily limited the further research and clinical application. Herein, (−)-gochnatiolide B was synthesized beginning with dehydrocostuslactone in four steps with a total yield of 26%. MTT assays showed that (−)-gochnatiolide B inhibited the growth of vast majority of human cancer cells especially bladder cancer cells. Mechanistically, (−)-gochnatiolide B induced the increased expression of pro-apoptotic proteins and the decreased expression of anti-apoptosis proteins and further resulted in apoptosis of T24 cells. (−)-Gochnatiolide B induced G1 arrest which associated with SKP2 downregulation, leading to p27/Kip1 accumulation and downregulation of cyclin D1 in T24 cells. Furthermore, in vivo studies showed that (−)-gochnatiolide B remarkably inhibited tumor growth by 81% compared with vehicle control. Taken together, (−)-gochnatiolide B exhibits inhibitory activity against bladder cancer cells both in vitro and in vivo by inducing apoptosis, which suggests that (−)-gochnatiolide B could be an important candidate compound for prevention and treatment of bladder cancer.
Highlights
Bladder cancer with the highest recurrence rate among solid tumors, is the most frequent malignancy of the urinary tract and the second primary cause of death in genitourinary cancer[1]
Natural products and their derivatives have become a precious source of drug discovery in recent decades. (−)-Gochnatiolide B, a guaianolide-type sesquiterpenoid dimer, was first isolated from the root of Gochnatia pomculat[3] and has previously been synthesized from a monomer dehydrozaluzanin C which was prepared from sesquiterpene natural product α-santonin in 11 steps with a low yield[4,5]
Compound 3 was ulteriorly oxidized by Dess-Martin periodinane oxidation to afford dehydrozaluzanin C (4) in excellent yield. (−)-Gochnatiolide B (1) was prepared from silyl enol ether 5 which was generated by treating 4 with hexamethyldisilazane (HMDS) and trimethylsilyl iodide (TMSI), in the presence of Pd(OAc)[2], CuCl and four times equivalent 4 through one-pot cascade transformations including inter-molecular Diels-Alder cycloaddition, Saegusa oxidation, and radical-mediated allylic oxidation[4] with 35% yield
Summary
Bladder cancer with the highest recurrence rate among solid tumors, is the most frequent malignancy of the urinary tract and the second primary cause of death in genitourinary cancer[1]. There is an urgent need to consider diverse and neoteric methods for treatment and prevention of bladder cancer. Natural products and their derivatives have become a precious source of drug discovery in recent decades. (−)-Gochnatiolide B, a guaianolide-type sesquiterpenoid dimer, was first isolated from the root of Gochnatia pomculat[3] and has previously been synthesized from a monomer dehydrozaluzanin C which was prepared from sesquiterpene natural product α-santonin in 11 steps with a low yield[4,5]. Lei and co-workers reported that ainsliadimer A, a sesquiterpene lactone dimer, targeted Cysteine 46 of IKKα/β to inhibit NF-κB signaling, leading to induction of cell death of various types of cancer cells, suppression of tumor growth in vivo, and induction of endotoxin-mediated inflammatory responses[6]. In an EJ xenograft tumor model, (−)-gochnatiolide B resulted in tumor regression by 81% compared with vehicle control
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