Asymmetric synthesis and anti-tumor properties of conformationally constrained analogues of (S)-and (R)-goniothalamin

Thesis (Master)--İzmir Institute of Technology, Chemistry, İzmir, 2008Includes bibliographical references (leaves: 60-62)Text in English; Abstract: Turkish and Englishxiii, 69 leavesNaturally isolated 5-substituted-a,B-unsaturated-.-lactones gained great attention of researchers due to their cytotoxic and anti-tumor properties. Styryl lactones are the most interesting members of this group of naturally available compounds. One of the well-known and important example for styryl lactone is goniothalamin, which shows cytotoxicity against variety of cancer cell lines. This cytotoxic property was shown to be selective for cancer cell lines with no significant cytotoxicity toward non-malignant cells. Recent structure activity relationship (SAR) studies on goniothalamin shows that R configuration on its stereogenic center, trans double bonded linker and Michael acceptor parts of the molecules are essential for its cytotoxic activity. In this study conformationally constrained analogues of (S)- and (R)-goniothalamin were synthesized. Syntheses were started with the catalytic asymmetric allylation of benzaldehyde, naphthaldehyde and quinaldehyde derivatives in the first step, then formed alcohols were acrylated with acryloyl chloride to yield the corresponding esters, in the last step, ring closing metathesis with Grubbs. catalyst yielded the target molecules. Meanwhile, in this study the synthesized 5-aryl-substituted-a,B-unsaturated-S-lactones were tested to determine their cytotoxicity against MCF-7, PC-3, DU-145 and LNCAP cancer cell lines

Asymmetric synthesis and anti-tumor properties of conformationally constrained analogues of (S)-and (R)-goniothalamin

Thesis (Master)--İzmir Institute of Technology, Chemistry, İzmir, 2008Includes bibliographical references (leaves: 60-62)Text in English; Abstract: Turkish and Englishxiii, 69 leavesNaturally isolated 5-substituted-a,B-unsaturated-.-lactones gained great attention of researchers due to their cytotoxic and anti-tumor properties. Styryl lactones are the most interesting members of this group of naturally available compounds. One of the well-known and important example for styryl lactone is goniothalamin, which shows cytotoxicity against variety of cancer cell lines. This cytotoxic property was shown to be selective for cancer cell lines with no significant cytotoxicity toward non-malignant cells. Recent structure activity relationship (SAR) studies on goniothalamin shows that R configuration on its stereogenic center, trans double bonded linker and Michael acceptor parts of the molecules are essential for its cytotoxic activity. In this study conformationally constrained analogues of (S)- and (R)-goniothalamin were synthesized. Syntheses were started with the catalytic asymmetric allylation of benzaldehyde, naphthaldehyde and quinaldehyde derivatives in the first step, then formed alcohols were acrylated with acryloyl chloride to yield the corresponding esters, in the last step, ring closing metathesis with Grubbs. catalyst yielded the target molecules. Meanwhile, in this study the synthesized 5-aryl-substituted-a,B-unsaturated-S-lactones were tested to determine their cytotoxicity against MCF-7, PC-3, DU-145 and LNCAP cancer cell lines

6-Bicycloaryl substituted (S)- and (R)-5,6-dihydro-2H-pyran-2-ones: Asymmetric synthesis, and anti-proliferative properties

(R)-Goniothalamin, is a member of styryl lactones, possesses selective cytotoxicity against cancer cell lines. In this work, replacement of styryl substituent with 2-naphthyl and 3-quinoyl gave new analogues which may have less conformational changes compared to the lead compound. Anti-proliferative tests indicated that 2-naphthyl substituted (R)-5,6-dihydro-2H-pyran-2-one has slightly better cytotoxicity than (R)-goniothalamin. To clarify the effect of 2-naphthyl substituent additional aryl substituted (R)-5,6-dihydro-2H-pyran-2-ones have been synthesized enantioselectively and tested against PC-3 and MCF-7 cell lines.TUBITAK (105T429

Michael acceptor properties of 6-bicycloaryl substituted (R)-5,6-dihydro-2H-pyran-2-ones

The mechanism of action for α,β-unsaturated lactones can be explained by their Michael acceptor properties. They have the potential of being covalently binding inhibitors by accepting nucleophiles from target proteins. In this work, Michael addition reactions of ethanethiol with 6-bicycloaryl substituted 5,6-dihydro-2H-pyran-2-ones were studied to explore the existence of such interactions. Three of the Michael addition products were isolated and tested over PC3 (human prostate cancer) and MCF-7 (human breast adenocarcinoma) cancer cell lines and no cytotoxicity was observed. It was revealed that biological activity depends on the existence of a Michael acceptor, but potency probably depends upon the 3D structure of the substituent on lactone ring. The primary chemical-quantum properties of the lactones were also calculated using the Spartan'08 computer program. © 2010 Elsevier Inc. All rights reserved.TÜBİTAK-TBAG Research Grant 105T42