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ABSTRACT: Many types of cancer, including glioma, melanoma, NSCLC, among others, are resistant to apoptosis induction and poorly responsive to current therapies with propaptotic agents. We describe a series of 2,3-disubstituted indoles, which display cytostatic rather than cytotoxic effects in cancer cells, and serve as a new chemical scaffold to develop anticancer agents capable of combating apoptosis-resistant cancers associated with dismal prognoses.
Bioorganic & medicinal chemistry letters 04/2013; · 2.65 Impact Factor
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ABSTRACT: It is widely recognized that the evasion of apoptotic cell death is one of the hallmarks of cancer. For many years cytotoxic agents have been developed to target apoptotic cell death as a main method of treating cancer. However, the occurrence of cellular defects involving the apoptotic machinery in many cancers has resulted in an acquired resistance to apoptotic cell death, undermining the effectiveness of chemotherapeutic agents. Over the past decade, research has revealed a growing number of cell death pathways that are not dependent on apoptosis. In addition, compounds specifically triggering these alternative cell death pathways have been identified and explored as novel cancer treatment options. These novel anticancer agents are critically discussed by the authors and, therefore, the current Perspective represents a resource for a practicing medicinal chemist looking for new opportunities to combat cancers resistant to the established pro-apoptotic therapeutic agents.
Journal of Medicinal Chemistry 03/2013; · 4.80 Impact Factor
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ABSTRACT: The title natural compound, isolated from var. King Alfred crystallizes as a hemihydrate, CHNO·0.5HO, with four crystallographically independent dioxolophenanthridinone mol-ecules and two crystallographically independent solvent water mol-ecules in the asymmetric unit. All four crystallographically independent dioxolophenanthridinone mol-ecules are geometrically very similar and differ only in the orientations of the three hy-droxy groups at the terminal cyclo-hexene rings. The five-membered dioxolane ring has a planar conformation (the r.m.s. deviations are 0.010, 0.019, 0.025 and 0.004 Å, for the four crystallographically independent molecules), and the six-membered dihydro-pyridone and cyclo-hexene rings adopt sofa conformations in each mol-ecule. The flattened structure of each dioxolophenanthridinone mol-ecule is supported by a strong intra-molecular O-H⋯O hydrogen bond. The N atom has a slightly pyramidalized configuration. In the crystal, the dioxolophenanthridinone mol-ecules form layers parallel to (101) with O-H⋯O and N-H⋯O hydrogen bonds linking the dioxolophenanthridinone mol-ecules both within and between the layers and the water mol-ecules, forming a three-dimensional framework. The absolute configurations of the chiral centers are 2, 3, 4 and 4a.
Acta Crystallographica Section E Structure Reports Online 01/2013; 69(Pt 1):o9-o10. · 0.35 Impact Factor
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Igor V Magedov,
Nikolai M Evdokimov,
Menuka Karki,
Amanda S Peretti,
Dustin T Lima,
Liliya V Frolova,
Mary R Reisenauer,
Anntherese E Romero,
Paul Tongwa,
Alexandr Fonari,
Jeff Altig,
Snezna Rogelj,
Mikhail Yu Antipin,
Charles B Shuster, Alexander Kornienko
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ABSTRACT: A variant structural skeleton of epipodophyllotoxin was synthesized and found to rival the natural cyclolignan in antiproliferative and microtubule destabilizing properties. This discovery leads to a new structural class of tubulin targeting agents.
Chemical Communications 09/2012; 48(84):10416-8. · 6.17 Impact Factor
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Igor V Magedov,
Artem S Kireev,
Aaron R Jenkins,
Nikolai M Evdokimov,
Dustin T Lima,
Paul Tongwa,
Jeff Altig,
Wim F A Steelant,
Severine Van slambrouck,
Mikhail Yu Antipin, Alexander Kornienko
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ABSTRACT: 4H-Pyrano-[2,3-b]naphthoquinone is a structural motif commonly found in natural products manifesting anticancer activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed a compound library based on this heterocyclic scaffold. We found that several library members displayed low micromolar antiproliferative activity and induced apoptosis in human cancer cells. Selected compounds showed promising activity against cancer cell lines resistant to proapoptotic stimuli, demonstrating their potential in treating cancers with dismal prognoses.
Bioorganic & medicinal chemistry letters 07/2012; 22(16):5195-8. · 2.65 Impact Factor
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ABSTRACT: Plants of the Amaryllidaceae family have been under intense scrutiny for the presence of the specific metabolites responsible
for the medicinal properties associated with them. The study began in 1877 with the isolation of alkaloid lycorine from Narcissus pseudonarcissus and since then more than 100 alkaloids, exhibiting diverse biological activities, have been isolated from the Amaryllidaceae
plants. Based on the present scientific evidence, it is likely that isocarbostyril constituents of the Amaryllidaceae, such
as narciclasine, pancratistatin and their congeners, are the most important metabolites responsible for the therapeutic benefits
of these plant species in the folk medical treatment of cancer. Notably, Narcissus poeticus L., used by the ancient Greek physicians, is now known to contain about 0.12g of narciclasine per kg of fresh bulbs. The
focus of the present research work is the chemistry and biology of these compounds as specifically relevant to their potential
use in medicine. In particular, the anticancer evaluation of lycorine, narciclasine as well as of other Amaryllidaceae alkaloids
and their synthetic derivatives are presented in this paper. The structure–activity relationships among some groups of Amaryllidaceae
alkaloids will be discussed.
Phytochemistry Reviews 04/2012; 8(2):449-459. · 4.33 Impact Factor
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ABSTRACT: The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.
Medicinal Research Reviews 03/2012; · 10.70 Impact Factor
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Giovanni Luchetti,
Robert Johnston,
Véronique Mathieu,
Florence Lefranc,
Kathryn Hayden,
Anna Andolfi,
Delphine Lamoral-Theys,
Mary R Reisenauer,
Cody Champion,
Stephen C Pelly,
Willem A L van Otterlo,
Igor V Magedov,
Robert Kiss,
Antonio Evidente,
Snezna Rogelj, Alexander Kornienko
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ABSTRACT: The Amaryllidaceae alkaloid bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine's natural crinine-type congeners, were evaluated in vitro against a panel of cancer cell lines with various levels of resistance to pro-apoptotic stimuli. Bulbispermine, haemanthamine, and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited notable growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion; they displayed similar potencies in both cell types, indicating that the induction of apoptosis is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis-resistant cancers and glioblastoma in particular.
ChemMedChem 03/2012; 7(5):815-22. · 3.15 Impact Factor
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ABSTRACT: A multicomponent reaction of 3-aminopyrazol-5-ones with substituted salicylic aldehydes and acetylacetic ester leading to the formation of novel 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones was discovered. The elucidation of the reaction scope revealed that 5-aminopyrazoles, 3-amino-1,2,4-triazoles and 6-aminouracil could be used as the heterocyclic amine component. Selected heterocyclic products were found to possess notable antibacterial activities.
Tetrahedron Letters 12/2011; 52(49):6643-6645. · 2.68 Impact Factor
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Nikolai M Evdokimov,
Delphine Lamoral-Theys,
Véronique Mathieu,
Anna Andolfi,
Liliya V Frolova,
Stephen C Pelly,
Willem A L van Otterlo,
Igor V Magedov,
Robert Kiss,
Antonio Evidente, Alexander Kornienko
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ABSTRACT: As a continuation of our studies aimed at the development of a new cytostatic agent derived from an Amaryllidaceae alkaloid lycorine, we synthesized 32 analogues of this natural product. This set of synthetic analogues included compounds incorporating selective derivatization of the C1 versus C2 hydroxyl groups, aromatized ring C, lactamized N6 nitrogen, dihydroxylated C3-C3a olefin functionality, transposed olefin from C3-C3a to C2-C3 or C3a-C4, and C1 long-chain fatty esters. All synthesized compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines including those exhibiting resistance to proapoptotic stimuli and representing solid cancers associated with dismal prognoses, such as melanoma, glioblastoma, and non-small-cell lung cancer. Most active analogues were not discriminatory between cancer cells displaying resistance or sensitivity to apoptosis, indicating that these compounds are thus able to overcome the intrinsic resistance of cancer cells to pro-apoptotic stimuli. 1,2-Di-O-allyllycorine was identified as a lycorine analogue, which is 100 times more potent against a U373 human glioblastoma model than the parent natural product. Furthermore, a number of synthetic analogues were identified as promising for the forthcoming in vivo studies.
Bioorganic & medicinal chemistry 12/2011; 19(23):7252-61. · 2.82 Impact Factor
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ABSTRACT: An unprecedented application of aryliodine (III) diacetates as substrates in Pd-Ag catalyzed arylation of alkenes is described. The mechanistic studies revealed that the binary Pd-Ag catalysis leads to the decomposition of aryliodine (III) diacetates to oxygen and aryl iodides followed by arylation of alkenes forming Heck-type products. Under optimized conditions both electron-rich and electron-deficient alkenes undergo arylation in high yields. Advantageously, the reaction proceeds smoothly in water as a solvent and neither organic ligands nor inert atmosphere are required.
Tetrahedron Letters 08/2011; 52(33):4327-4329. · 2.68 Impact Factor
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ABSTRACT: A novel reaction of indole with aryldiazonium salts leading to the formation of 2-aryl-3-(arylazo)indoles was discovered. The products were found to possess potent anti-MRSA and anti-LLVRE activities. The SAR studies indicate that the potentially metabolically labile azo functionality can be replaced with ether oxygen and thioether sulfur atoms without any loss of activity.
Bioorganic & medicinal chemistry letters 08/2011; 21(16):4720-3. · 2.65 Impact Factor
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ABSTRACT: The synthesis of two C-1 analogues of pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines.
Bioorganic & medicinal chemistry letters 08/2011; 21(16):4750-2. · 2.65 Impact Factor
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Igor V Magedov,
Liliya Frolova,
Madhuri Manpadi,
Uma devi Bhoga,
Hong Tang,
Nikolai M Evdokimov,
Olivia George,
Kathy Hadje Georgiou,
Steffen Renner,
Matthäus Getlik,
Tiffany L Kinnibrugh,
Manuel A Fernandes,
Severine Van slambrouck,
Wim F A Steelant,
Charles B Shuster,
Snezna Rogelj,
Willem A L van Otterlo, Alexander Kornienko
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ABSTRACT: Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on β-tubulin, provided a theoretical understanding of these successful experimental findings.
Journal of Medicinal Chemistry 06/2011; 54(12):4234-46. · 4.80 Impact Factor
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Nikolai M Evdokimov,
Severine Van Slambrouck,
Petra Heffeter,
Lee Tu,
Benjamin Le Calvé,
Delphine Lamoral-Theys,
Carla J Hooten,
Pavel Y Uglinskii,
Snezna Rogelj,
Robert Kiss,
Wim F A Steelant,
Walter Berger,
Jeremy J Yang,
Cristian G Bologa, Alexander Kornienko,
Igor V Magedov
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ABSTRACT: After the initial discovery of antiproliferative and apoptosis-inducing properties of a camptothecin-inspired pentacycle based on a 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine scaffold, a library of its analogues as well as their oxidized planar counterparts were prepared utilizing a practical multicomponent synthetic protocol. The synthesized compounds exhibited submicromolar to low micromolar antiproliferative potencies toward a panel of human cancer cell lines. Biochemical experiments are consistent with the dihydropyridine library members undergoing intracellular oxidation to the corresponding planar pyridines, which then inhibit topoisomerase II activity, leading to inhibition of proliferation and cell death. Because of facile synthetic preparation and promising antitopoisomerase activity, both the dihydropyridine and planar pyridine-based compounds represent a convenient starting point for anticancer drug discovery.
Journal of Medicinal Chemistry 03/2011; 54(7):2012-21. · 4.80 Impact Factor
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ABSTRACT: Privileged medicinal scaffolds based on the structures of tetra- and pentasubstituted 2-aminopyrroles were prepared via one-pot multicomponent reactions of structurally diverse aldehydes and N-(aryl-, hetaryl-, alkylsulfonamido)acetophenones with activated methylene compounds. This methodology was used in a four-step synthesis of alkaloids rigidins A, B, C, and D in overall yields of 61%, 58%, 60%, and 53%, respectively. Of these, rigidins B, C, and D were synthesized for the first time.
Organic Letters 01/2011; 13(5):1118-21. · 5.86 Impact Factor
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Gwendoline Van Goietsenoven,
Jenna Hutton,
Jean-Paul Becker,
Benjamin Lallemand,
Francis Robert,
Florence Lefranc,
Christine Pirker,
Guy Vandenbussche,
Pierre Van Antwerpen,
Antonio Evidente,
Walter Berger,
Martine Prévost,
Jerry Pelletier,
Robert Kiss,
Terri Goss Kinzy, Alexander Kornienko,
Véronique Mathieu
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ABSTRACT: Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through the targeting of eEF1A elongation factor with narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC(50) growth inhibitory values between 30-100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, narciclasine also significantly improves (P=0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEF1A targeting with narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (≥200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that narciclasine directly binds to human recombinant and yeast-purified eEF1A in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEF1A is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of narciclasine. -
The FASEB Journal 11/2010; 24(11):4575-84. · 5.71 Impact Factor
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Gwendoline Van Goietsenoven,
Anna Andolfi,
Benjamin Lallemand,
Alessio Cimmino,
Delphine Lamoral-Theys,
Thierry Gras,
Amina Abou-Donia,
Jacques Dubois,
Florence Lefranc,
Véronique Mathieu, Alexander Kornienko,
Robert Kiss,
Antonio Evidente
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ABSTRACT: Fifteen Amaryllidaceae alkaloids (1-15) were evaluated for their antiproliferative activities against six distinct cancer cell lines. Several of these natural products were found to have low micromolar antiproliferative potencies. The log P values of these compounds did not influence their observed activity. When active, the compounds displayed cytostatic, not cytotoxic activity, with the exception of pseudolycorine (3), which exhibited cytotoxic profiles. The active compounds showed similar efficacies toward cancer cells irrespective of whether the cell lines were responsive or resistant to proapoptotic stimuli. Altogether, the data from the present study revealed that lycorine (1), amarbellisine (6), haemanthamine (14), and haemanthidine (15) are potentially useful chemical scaffolds to generate further compounds to combat cancers associated with poor prognoses, especially those naturally resistant to apoptosis, such as glioblastoma, melanoma, non-small-cell lung, and metastatic cancers.
Journal of Natural Products 07/2010; 73(7):1223-7. · 3.13 Impact Factor
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Delphine Lamoral-Theys,
Laurent Pottier,
Frédéric Kerff,
François Dufrasne,
Fabien Proutière,
Nathalie Wauthoz,
Philippe Neven,
Laurent Ingrassia,
Pierre Van Antwerpen,
Florence Lefranc,
Michel Gelbcke,
Bernard Pirotte,
Jean-Louis Kraus,
Jean Nève, Alexander Kornienko,
Robert Kiss,
Jacques Dubois
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ABSTRACT: A series of 33 novel divanillates and trivanillates were synthesized and found to possess promising cytostatic rather than cytotoxic properties. Several compounds under study decreased by >50% the activity of Aurora A, B, and C, and WEE1 kinase activity at concentrations <10% of their IC(50) growth inhibitory ones, accounting, at least partly, for their cytostatic effects in cancer cells and to a lesser extent in normal cells. Compounds 6b and 13c represent interesting starting points for the development of cytostatic agents to combat cancers, which are naturally resistant to pro-apoptotic stimuli, including metastatic malignancies.
Bioorganic & medicinal chemistry 06/2010; 18(11):3823-33. · 2.82 Impact Factor
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ABSTRACT: An efficient synthesis of C-1 derivatives of 7-deoxypancratistatin is reported. The key steps include the following: selective opening of an epoxide with aluminum acetylide in the presence of an aziridine; solid-state silica-gel-catalyzed opening of an aziridine; and oxidative cleavage of a phenanthrene core and its recyclization to phenanthridone to provide the key C-1 aldehyde 22. The conversion of this aldehyde to C-1 acetoxymethyl and C-1 hydroxymethyl derivatives is described along with the evaluation of their biological activity against several cancer cell lines and in an apoptosis study. The C-1 acetoxymethyl derivative has shown promising activity comparable to that of the natural product. In addition, a total synthesis of trans-dihydrolycoricidine and a formal total synthesis of 7-deoxypancratistatin are reported from aldehyde 22. Detailed experimental and spectral data are provided for all new compounds.
The Journal of Organic Chemistry 04/2010; 75(9):3069-84. · 4.45 Impact Factor
