63 research outputs found
Palladium-catalyzed coupling of N-tosylhydrazones with ortho substituted aryl halides: synthesis of 4-arylchromenes and related heterocycles
International audienceA convenient and efficient procedure for the synthesis of 4-arylchromenes, thiochromenes, and related heterocycles via a four step-sequence has been developed. The first three steps, which involve hydration of alkynes, hydrazones formation, and their Pd-coupling with ortho substituted aryl halides, furnished stereoselectively Z-trisubstituted olefins without any purification of the intermediates generated in each stage. These latter proved to be suitable precursors, in the last step, for the synthesis of the desired heterocycles of biological interest.
Regioselective hydrostannation of diarylalkynes directed by a labile ortho bromine atom: An easy access to stereodefined triarylolefins, hybrids of combretastatin A-4 and isocombretastatin A-4
International audienceA series of triarylolefins bearing the combretastatin A-4 and the isocombretastatin A-4 cores were synthesized and evaluated. The cooperative ortho-effect of a labile bromine atom in the regioselective hydrostannation of unsymmetrical diarylalkynes leading to stereo-defined triarylolefins is presented
Conformationnally restricted naphthalene derivatives type isocombretastatin A-4 and isoerianin analogues: Synthesis, cytotoxicity and antitubulin activity
International audienceA novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted-analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumor cell lines was observed at a nanomolar level with dihydronaphtalenes 1d,e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure activity relationships are also considered. These compounds exhibited a significant inhibitory activity toward tubulin polymerization (IC50 = 2-3 ïM), comparable to that of isoCA-4. The effect of the lead compounds 1e and 2c on the cancer cells tested was associated with cell cycle arrest in the G2/M phase. Docking studies reveal that these compounds showed a binding mode similar to those observed with their non-constraint isoCA-4 and isoerianin congeners
Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted iso combretastatin A-4 analogs
International audienceA series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogues according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on ïą-tubulin
Six-membered ring systems: with O and/or S atoms
A large variety of publications have emerged in 2012 involving O- and S-6-
membered ring systems. The increasing number of reviews and other communica-
tions dedicated to natural and synthetic derivatives and their biological significance
highlights the importance of these heterocycles.
Reviews on natural products involve biosynthesis and isolation of enantiomeric
derivatives h12AGE4802i, biosynthesis, isolation, synthesis, and biological studies
on the pederin family h12NPR980i and xanthones obtained from fungi, lichens,
and bacteria h12CR3717i and on the potential chemotherapeutic value of phyto-
chemical products and plant extracts as antidiabetic h12NPR580i, antimicrobial,
and resistance-modifying agents h12NPR1007i. A more specific review covers a
structureâactivity relationship of endoperoxides from marine origin and their antitry-
panosomal activity h12OBC7197i.
New synthetic routes to naturally occurring, biologically active pyran derivatives
have been the object of several papers. Different approaches have been discussed for
the total synthesis of tetrahydropyran-containing natural products (")-zampanolide
h12CEJ16868, 12EJO4130, 12OL3408i, (")-aspergillides A and B h12H(85)587,
12H(85)1255, 12TA252i, (ĂŸ)-neopeltolide h12JOC2225, 12JOC9840, 12H(85)
1255i, or their macrolactone core h12OBC3689, 12OL2346i. The total synthesis
of bistramide A h12CEJ7452i and (ĂŸ)-kalihinol A h12CC901i and the stereoselec-
tive synthesis of a fragment of bryostatin h12S3077, 12TL6163i have also been sur-
veyed. Other papers relate the total synthesis of naturally occurring carbocyclic and
heterocyclic-fused pyran compounds, such as (")-dysiherbaine h12CC6295i, penos-
tatin B h12OL244i, Greek tobacco lactonic products, and analogues h12TL4293i
and on the structurally intriguing limonoids andhraxylocarpins AâE h12CEJ14342i.
The stereocontrolled synthesis of fused tetrahydropyrans was used in the preparation
of blepharocalyxin D h12AGE3901i.
Polyphenolic heterocyclic compounds have also received great attention in 2012.
The biological activities and the chemistry of prenylated caged xanthones
h12PCB78i, the occurrence of sesquiterpene coumarins h12PR77i, and the medicinal properties of the xanthone mangiferin h12MRME412i have been reviewed.
An overview on the asymmetric syntheses of flavanones and chromanones
h12EJO449i, on the synthesis and reactivity of flavones h12T8523i and xanthones
h12COC2818i, on the synthesis and biosynthesis of biocoumarins h12T2553i, and on
the synthesis and applications of flavylium compounds h12CSR869i has been discussed.
The most recent developments in the synthesis and applications of sultones, a
very important class of sulfur compounds, were reported h12CR5339i.
A review on xanthene-based fluorescent probes for sensing cations, anions, bio-
logical species, and enzyme activity has described the spiro-ring-opening approach
with a focus on the major mechanisms controlling their luminescence behavior
h12CR1910i. The design and synthesis of other derivatives to be used as sensors of
gold species h12CC11229i and other specific metal cations h12PC823i have also
been described. Recent advances related to coumarin-derived fluorescent chemosen-
sors for metal ions h12COC2690i and to monitoring in vitro analysis and cellular
imaging of monoamine oxidase activity h12CC6833i have been discussed.
The study of various organic chromophores allowed the synthesis of novel dica-
tionic phloroglucinol-type bisflavylium pigments h12SL2053i, and the optical and
spectroscopic properties of several synthetic 6-aryldibenzo[b,d]pyrylium salts were
explored h12TL6433i.
Discussion of specific reactions leading to O- and S-membered heterocyclic
compounds covers intramolecular radical cyclization h12S2475i and asymmetric
enamine and dienamine catalysis h12EJO865i, oxa-Michael h12CSR988i and dom-
ino Knoevenagelâhetero-DielsâAlder (hDA) reactions h12T5693i, and the versatility
in cycloadditions as well as nucleophilic reactions using o-quinones h12CSR1050i.
The use of specific reagents relevant to this chapter includes molecular iodine
h12CEJ5460, 12COS561i, samarium diiodideâwater for selective reductive transfor-
mations h12CC330i, o-quinone methides as versatile intermediates h12CEJ9160i,
InCl3 as catalyst h12T8683i, and gold and platinum p-acid mediated insertion of
alkynes into carbonâheteroatom s-bonds h12S3401i.
The remainder of this chapter discusses the most studied transformations on
O- and S-6-membered heterocycles
Design, synthesis and biological evaluation of conformationally restricted analogues of /i//so/combretastatin A-4 as potential antitumoral agents
Les rĂ©sistances aux traitements actuels contre le cancer imposent de trouver de nouvelles cibles thĂ©rapeutiques. Une de ces cibles est le rĂ©seau vasculaire assurant un apport suffisant en nutriments et en oxygĂšne Ă la tumeur, et permettant lâapparition de mĂ©tastases. DĂ©truire la vascularisation de la tumeur par lâutilisation dâagents antivasculaires (VDA)revient Ă lâasphyxier et Ă lâaffamer, inhibant ainsi la prolifĂ©ration des cellules tumorales et empĂȘchant le processus mĂ©tastatique. Lâobjectif de ce travail de thĂšse a Ă©tĂ© dâĂ©tudier des analogues contraints de lâisocombrĂ©tastatine A-4 (isoCA-4), une molĂ©cule phare du laboratoire, ayant un excellent pouvoir dâinhibition de la polymĂ©risation de la tubuline et prĂ©sentant une activitĂ© antivasculaire. Ces structures dont la double liaison est incluse dans diffĂ©rents types de cycles C,ont Ă©tĂ© Ă©tudiĂ©es Ă©galement afin dâĂ©valuer lâinfluence de lâangle diĂšdre formĂ© par les noyaux A et B sur les activitĂ©s biologiques des divers types de structures. PrĂ©alablement sĂ©lectionnĂ©s par modĂ©lisation molĂ©culaire, ces analogues contraints sont de type 1-arylnaphtalĂšne, 5-arylbenzoxĂ©pine ou 4-arylchromĂšne et ont Ă©tĂ© prĂ©parĂ©s par des voies dâ accĂšs originales dĂ©veloppĂ©es dans le cadre de cette thĂšse. Parmi les composĂ©s synthĂ©tisĂ©s, lâanalogue de type benzoxĂ©pine 3-53est aussi cytotoxique que lâisoCA-4 et possĂšde un pouvoir dâinhibition de la polymĂ©risation de la tubuline Ă©quivalent. Une Ă©valuation plus poussĂ©e de son profil biologique, ainsi que celle des meilleurs reprĂ©sentants de chaque sĂ©rie chimique est actuellement en cours.Most tumor cells rely on an efficient vascular supply for their survival, making the tumor vasculature an attractive target for anti-cancer therapy. This thesis aimed at the design and synthesis of constrained analogues of isocombretastatin A-4(isoCA-4), an antivascular agent developed in the laboratory, which exerts excellent cytotoxicities against a large panel ofcancer cell lines, and strongly inhibits tubulin polymerization. Conformationally restricted analogues of isoCA-4,featuring 1-arylnaphthalene, 5-arylbenzoxepine or 4-arylchromene skeletons were designed by computational studies andprepared by novel synthetic strategies. Of all synthesized compounds, benzoxepine analogue 3-53 strongly inhibits tubulinpolymerization and shows excellent cytotoxicities against several human cancer cell lines
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