Short communicationNovel oleanolic vinyl boronates: Synthesis and antitumor activity
Graphical abstract
Highlights
► A series of new oleanolic vinyl boronates have been synthesized. ► Their effects on the proliferation of cancer cells were evaluated. ► Some of the compounds induced caspase-dependent apoptotic tumor cell death. ► Two compounds inhibited the proteasomal activity of Jurkat cells. ► Boron-containing oleananes are templates for the development of anticancer drugs.
Introduction
Pentacyclic triterpenoids are secondary plant metabolites found in fruit peel, leaves and stem bark [1], [2], [3]. Their potential interest in cancer has now been well demonstrated by the successful clinical utilities of oleanolic acid (OA), glycyrrhetic acid, asiaticoside, and carbenoxolone as market drugs [4]. OA bears an impressive myriad of reported biological activities [5], [6], [7] including antibacterial [8], antiparasitic [9], antiosteoporotic [10], antifertility [11], antihypertensive [12], antihyperlipidemic [13], antidiabetic [14], immunomodulatory [15], anti-inflammatory [16], antinociceptive [17], gastro and hepatoprotective [18], and antiviral [19]. Chemical modifications of OA to produce derivatives have been successful in improving not only its activity but also its pharmacokinetic properties. Although quite many OA derivatives have now been reported in the literature, none have been synthesized bearing boron. Boron chemistry remained relatively unexploited in the medicinal chemistry arena until the FDA approved the boronic acid proteasome inhibitor bortezomib (Velcade®) for the treatment of multiple myeloma and non-Hodgkin lymphoma, in 2003 [20]. Since then, some promising compounds have been developed and tested among which is PT-100 (Val-boroPro, Talabostat) that targets dipeptidyl peptidases, such as fibroblast activation protein. In 2004, a phase II clinical trial of PT-100 was launched for the treatment of advanced non-small cell lung cancer [21]. However, it has been placed on hold in 2007 due to efficacy issues. The compound has also been recently studied on Phase I and II clinical trials in other cancers including melanoma and brain tumors.
The physical, chemical and biological properties of boron offer medicinal chemists an excellent opportunity to explore and pioneer new areas of drug discovery [22]. Boron is non-toxic, has Lewis acid behavior due to its empty p-orbital, and bears electrophilic character. Its empty p-orbital can be occupied by a lone pair of electrons, allowing it to form dative bonds with biological nucleophiles of enzyme residues (such as serine) and hydroxyl groups from carbohydrates and nucleic acids. Thus, several boron-containing compounds, including analogs of natural products such as β-lactamic antibiotics and curcumin, have been reported to be inhibitors of serine and aspartic proteases, metalloproteases, γ-glutamyl transpeptidase, arginase, surfactin synthetase C-terminal thioesterase, cysteine proteases, tyrosine kinases, as well as to be threonine-based inhibitors [22]. In continuation of our efforts to design new triterpenoids as anticancer agents [2], [23], [24], [25], [26], [27], [28], [29], we have successfully prepared a series of novel oleanane-type pentacyclic triterpenoids bearing a boronate ester moiety. We have screened the compounds for cytotoxic activity against a panel of hematological-based and solid tumor cell lines and against non-tumoral human fibroblasts. We have also studied their effects on cell cycle, ability to induce apoptosis and to inhibit proteasomal activity in leukemia Jurkat cells.
Section snippets
Chemistry
The synthesis of the oleanolic vinyl boronates 4–11 started from oleanolic acid 1 (Scheme 1) and exploited the palladium-catalyzed cross-coupling reaction of bis(pinacolato)diboron (B2pin2) with 1-alkenyl (vinyl) triflates in the presence of di-t-butyl-methylpyridine (DTBMP) [30]. The 28-carboxyl group was first protected as the methyl ester [31] to afford compound 2 which was further reacted with triflic anhydride (Tf2O) in the presence of base to give the vinyl triflate intermediate 3, in 83%
Conclusions
We herein report the synthesis and structural elucidation of a series of novel oleanane-type pentacyclic triterpenoids bearing a boronate ester moiety, and the study of their antitumoral effects. We have found that the oleanolic vinyl boronates bearing an amide bond at C28 7, 9, and 11 could inhibit the proliferation of the solid- and hematological-based tumor cell lines tested and that this inhibition was selective toward tumor cell lines. In addition, the compounds induced caspase-dependent
Chemistry
All reagents were obtained from Sigma–Aldrich Co. For thin layer chromatography (TLC) analysis, Kieselgel 60HF254/Kieselgel 60G was used. IR spectra were obtained using a JASCO FT/IR-420 spectrophotometer (FTIR-ATR). NMR spectra were obtained using a Brucker Digital NMR—Avance 400 apparatus spectrometer, in CDCl3 with Me4Si as the internal standard. NMR data was obtained at the Nuclear Magnetic Resonance Laboratory of the Coimbra Chemistry Centre (www.nmrccc.uc.pt), Universidade de Coimbra,
Acknowledgments
Jorge A.R. Salvador thanks Universidade de Coimbra for financial support. Vânia M. Moreira thanks Fundação para a Ciência e a Tecnologia for financial support (SFRH/BPD/45037/2008). The authors would like to acknowledge Alessandro Canella at the Department of Biochemistry and Molecular Biology, University of Ferrara, Italy and Teresa Gagliano, Federico Tagliati, and Degli Uberti EC at the Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara,
References (57)
Oleanolic and ursolic acid: research perspectives
J. Ethnopharmacol.
(2005)- et al.
Oleanolic acid
Phytochemistry
(2012) - et al.
Ursolic, oleanolic and betulinic acids: antibacterial spectra and selectivity indexes
J. Ethnopharmacol.
(2008) - et al.
Antileishmanial activity of isolated triterpenoids from Pourouma guianensis
Phytomedicine
(2004) - et al.
Synthesis and evaluation of a novel series of heterocyclic oleanolic acid derivatives with anti-osteoclast formation activity
Eur. J. Med. Chem.
(2009) - et al.
Antifertility effect in male rats of oleanolic acid, a triterpene from Eugenia jambolana flowers
J. Ethnopharmacol.
(1988) - et al.
Cardiotonic and antidysrhythmic effects of oleanolic and ursolic acids, methyl maslinate and uvaol
Phytomedicine
(2004) - et al.
Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension
Phytomedicine
(2003) - et al.
Antidiabetic activity of some pentacyclic acid triterpenoids, role of PTP-1B: in vitro, in silico, and in vivo approaches
Eur. J. Med. Chem.
(2011) - et al.
Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system
Phytomedicine
(2003)
Oleanolic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity
Eur. J. Pharmacol.
Oleanolic acid, a pentacyclic triterpene attenuates capsaicin-induced nociception in mice: possible mechanisms
Pharmacol. Res.
Gastroprotective and ulcer-healing activity of oleanolic acid derivatives: in vitro–in vivo relationships
Life Sci.
Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21waf1 and NOXA in pancreatic cancer cells
Bioorg. Med. Chem.
New betulinic acid derivatives induce potent and selective antiproliferative activity through cell cycle arrest at the S phase and caspase-dependent apoptosis in human cancer cells
Biochimie
Novel semisynthetic derivatives of betulin and betulinic acid with cytotoxic activity
Bioorg. Med. Chem.
Synthesis and structure–activity relationship study of novel cytotoxic carbamate and N-acylheterocyclic bearing derivatives of betulin and betulinic acid
Bioorg. Med. Chem.
Synthesis and activity of oleanolic acid derivatives, a novel class of inhibitors of osteoclast formation
Bioorg. Med. Chem. Lett.
Oxidations with potassium permanganate metal sulphates and nitrates. β-Selective epoxidation of Δ5-unsaturated steroids
Tetrahedron Lett.
The cytotoxic activity of ursolic acid derivatives
Eur. J. Med. Chem.
A new method for the conversion of secondary and tertiary amides to bridged orthoesters
Tetrahedron Lett.
Proteasome inhibitors: an expanding army attacking a unique target
Chem. Biol.
Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kB with antimyeloma activity in vitro and in vivo
Blood
Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-kB-regulated gene products and TAK1-mediated NF-kB activation
Blood
Synthesis and proteasome inhibition of glycyrrhetinic acid derivatives
Bioorg. Med. Chem.
New betulinic acid derivatives as potent proteasome inhibitors
Bioorg. Med. Chem. Lett.
Pentacyclic triterpene distribution in various plants – rich sources for a new group of multi-potent plant extracts
Molecules
Ursane-type pentacyclic triterpenoids as useful platforms to discover anticancer drugs
Nat. Prod. Rep.
Cited by (18)
Synthesis, characterization of novel isoindolinyl- and bis-isoindolinylphenylboronic anhydrides. Antiproliferative activity on glioblastoma cells and microglial cells assays of boron and isoindolines compounds
2019, Journal of Organometallic ChemistryCitation Excerpt :The importance of boron compounds have been increasing because of its several applications, the synthetic efforts to provide new molecules and due to their biological properties [1–5]. In fact, boron therapeutics showed different modes of inhibition for a variety of biological targets, the first classes of boron compounds reported antibiotic activity [6], boronic acid analogs of lysine and arginine have been reported as inhibitors for serine protease in the blood coagulation cascade [7], boronic compounds also have exhibited application in boron neutron capture therapy (BNCT) for the treatment of brain tumors like glioblastoma multiforme [8–11], as inhibitors of human Arginases I and II for the treatment of myocardial ischemia reperfusion injury [12], 2-APB as responsible for the store-operated calcium entry (SOCE) potentiation ability [13] and cytotoxic activity [14–18]. In the last few years, boron compounds become more frequent in the treatment of some types of inoperable and high malignancy cancers [19], as glioblastoma (GMB) that is the most common primary malignant tumor of the brain in adults, which is characterized by diffusely silent infiltration in the normal brain [9,20], which makes it impossible to detect it in a timely manner, it is often manifested by a single attack of progressive intensity headache in a few days.
Design, synthesis and biological evaluation of novel C-29 carbamate celastrol derivatives as potent and selective cytotoxic compounds
2017, European Journal of Medicinal ChemistryCitation Excerpt :Triterpenoids comprise a large and structurally diverse class of secondary metabolites that are distributed ubiquitously in plants [1,2]. The success of these natural products in cancer drug discovery is increasing continuously, as reflected by the exponential growth of scientific publications and patents in this field [3–11]. Celastrol is a natural quinone methide triterpenoid that was isolated from the traditional Chinese medicinal plant Tripterygium wilfordii Hook F., the extracts of which have been used in the treatment of autoimmune, inflammatory and neurodegenerative diseases, as well as in the treatment of many types of cancer [12–14].
Synthesis of oleanolic acid dimers linked at C-28 and evaluation of anti-tumor activity
2015, European Journal of Medicinal ChemistrySynthesis and biological evaluation of new oxadiazoline-substituted naphthalenyl acetates as anticancer agents
2014, European Journal of Medicinal ChemistryCitation Excerpt :In view of the above-mentioned facts, and inspired by the promising biological activities of naphthalenes, we set out to synthesize a series of novel substituted naphthalenes aiming at improving their anticancer activity and selectivity profile, through binding to an oxadiazoline moiety. The introduction of heterocyclic moieties in molecules has been proven advantageous in drug discovery, for the design of novel bioactive compounds [16–22]. In this regard, five-membered 1,3,4-oxadiazole heterocycles are known to be useful intermediates in organic synthesis [23–25] and to exhibit a wide range of biological activities such as antiviral [26], antimicrobial [15,27,28], anti-inflammatory [29] and antitrypanosomal [30] activities.
Synthesis and biological evaluation of novel aniline-derived asiatic acid derivatives as potential anticancer agents
2014, European Journal of Medicinal ChemistryCitation Excerpt :Natural products have provided a major source of therapeutic agents for human disease over the past century [1,2]. In recent years, a large number of terpenes has marked anticancer effects toward various types of cancer cell lines in vitro, some of them had been successfully developed for clinical use to treatment human cancers diseases in some therapeutic areas [3–12], especially the pentacyclic triterpenes including oleanolic acid (OA), glycyrrhetic acid, and carbenoxolone [13,14]. Therefore, development of novel pentacyclic triterpenes derivatives with better antitumor activities have greatly gained bioorganic chemists' interest.
Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: Preclinical and clinical evidence
2014, Cancer LettersCitation Excerpt :Olean-12-Eno[2,3-c] [1,2,5] oxadiazol-28-oic acid (OEOA), synthetic derivative of OA, induced G1 cell cycle arrest as well as differentiation in human leukemia cell lines, K562, HEL and JURKAT [62]. Three new active oleanolic vinyl bornates inhibited the growth of leukemia cells (Jurkat and K562) and Burkitt’s lymphoma cells (Jijoye) without concomitant inhibition of non-tumoral human fibroblasts [63]. CDDO primarily activated the extrinsic apoptotic pathway in myeloid leukemia cells [64].
- 1
Present address: Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Finland.