ABSTRACT
Natural sesterterpenolides, luffarin I and luffarin A, from Luffariella geometrica have been synthesized, and this is the first reported synthesis of luffarin A. The Yamaguchi esterification of the nor-diterpenic fragment, obtained from 2.8-15µM, with the appropriate furane alcohols yielded the necessary diene intermediates for the synthesis of the target molecules. The key strategic step in this synthesis was the ring-closing metathesis (RCM) reaction of the diene intermediates. This strategy allowed for the synthesis of 16-epi-luffarin I and analogues for structure-activity relationship (SAR) studies. The most active compound exhibited antiproliferative activity against a panel of six human solid tumour cell lines with [Formula: see text] values in the range 2.8-15 M.
Subject(s)
4-Butyrolactone/analogs & derivatives , Sesterterpenes/chemistry , Sesterterpenes/chemical synthesis , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , 4-Butyrolactone/pharmacology , Cell Line, Tumor , Cellular Reprogramming Techniques , Chemistry Techniques, Synthetic , Humans , Sesterterpenes/pharmacology , StereoisomerismABSTRACT
The first synthesis of luffarin L (1) and 16-epi-luffarin L (2) by a silicon-tethered ring closing metathesis as a key step has been achieved. The stereochemistry and absolute configuration of the natural sesterterpenolide luffarin L (1) and a new route for the stereoselective synthesis of sesterterpenolides with a luffarane skeleton have been established.
Subject(s)
Sesquiterpenes/chemical synthesis , Silicon/chemistry , Cyclization , Molecular Structure , Sesquiterpenes/chemistry , StereoisomerismABSTRACT
The first synthesis of Luffarin I, sesterterpenolide isolated from sponge Luffariella geometrica, has been accomplished from commercially available sclareol. The key strategy involved in this synthesis is the diastereoselective reduction of an intermediate ketone. Luffarin I against human solid tumor cell lines showed antiproliferative activities (GI50) in the range 12-17 µM.
Subject(s)
4-Butyrolactone/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Furans/chemical synthesis , Neoplasms/drug therapy , Sesterterpenes/chemical synthesis , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , 4-Butyrolactone/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Australia , Cell Line, Tumor , Cell Proliferation/drug effects , Diterpenes/chemistry , Furans/chemistry , Furans/pharmacology , Humans , Indicators and Reagents/chemistry , Molecular Conformation , Molecular Structure , Neoplasms/pathology , Osmolar Concentration , Pacific Ocean , Porifera/chemistry , Sesterterpenes/chemistry , Sesterterpenes/pharmacology , StereoisomerismABSTRACT
Sesterterpenes with a salmahyrtisane skeleton have been synthesized for the first time. (-)-Sclareol has been selected as a precursor for the synthesis of two novel natural products: salmahyrtisol A (1) and hippospongide A (2). Our results represent a biomimetic approach to obtaining salmahyrtisanes from hyrtiosanes. Salmahyrtisol A has shown an activity comparable to that of the standard anticancer drugs in the cell lines A549, HBL-100, HeLa, and SW1573.
Subject(s)
Antineoplastic Agents/pharmacology , Biomimetic Materials/pharmacology , Sesterterpenes/pharmacology , Terpenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Molecular Conformation , Sesterterpenes/chemical synthesis , Sesterterpenes/chemistry , Stereoisomerism , Structure-Activity Relationship , Terpenes/chemical synthesis , Terpenes/chemistryABSTRACT
A series of sesterterpenoid bioconjugates with phospholipids and polyunsaturated fatty acids (PUFAs) have been synthesized for biological activity testing as antiproliferative agents in several cancer cell lines. Different substitution analogues of the original lipidic ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) are obtained varying the sesterterpenoid in position 1 or 2 of the glycerol or a phosphocholine or PUFA unit in position 3. Simple bioconjugates of sesterterpenoids and eicosapentaenoic acid (EPA) have been obtained too. All synthetic derivatives were tested against the human tumour cell lines HeLa (cervix) and MCF-7 (breast). Some compounds showed good IC50 (0.3 and 0.2 µM) values against these cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Fatty Acids, Unsaturated/chemistry , Phospholipids/chemistry , Sesterterpenes/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Female , HeLa Cells , Humans , MCF-7 Cells , Phospholipid Ethers , Sesterterpenes/chemistry , Sesterterpenes/pharmacologyABSTRACT
A series of indole sesquiterpenes analogues of polyalthenol and pentacyclindole have been synthesized starting from ent-halimic acid in order to test their biological activity. These analogues include diverse oxidation levels at the sesquiterpenyl moiety and different functionalization on the indole ring. All synthetic derivatives were tested against a representative panel of Gram positive and Gram negative bacterial strains, and the human solid tumour cell lines A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). Overall, the compounds presented activity against the cancer cell lines. The resulting lead, displaying a polyalthenol scaffold, showed GI50 values in the range 1.2-5.7 µM against all cell lines tested.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antineoplastic Agents, Phytogenic/chemical synthesis , Drug Design , Indole Alkaloids/chemical synthesis , Indoles/chemical synthesis , Sesquiterpenes/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Indole Alkaloids/chemistry , Indole Alkaloids/pharmacology , Indoles/chemistry , Indoles/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Staphylococcus aureus/drug effectsABSTRACT
The natural product sesquiterpenyl indoles are structural hybrids from farnesyl pyrophosphate and tryptophan or its precursors, often with unusual and complex structural features, many of them with interesting biological activities. In this review the compounds of this class known until now are classified, a biosynthetic approach of each group is proposed and a review of the synthesis or synthetic approaches is communicated.
Subject(s)
Biological Products , Indoles , Sesquiterpenes , Biological Products/chemistry , Biological Products/metabolism , Indoles/chemistry , Indoles/metabolism , Molecular Structure , Polyisoprenyl Phosphates/chemistry , Sesquiterpenes/chemistry , Sesquiterpenes/metabolismABSTRACT
A Yamaguchi-type cyclization of 5 and subsequent photochemical oxidation of the furanic ring are the key steps in the first synthesis of the marine metabolite (+)-luffalactone 4 and its epimer at C-16, 16-epi-luffalactone, 27. With this work, we have successfully established the absolute configuration of the natural product. The key intermediate 5 was obtained from the easily accessible diacetate 6a/6b.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Lactones/chemical synthesis , Photochemistry , Cyclization , Heterocyclic Compounds, 3-Ring/chemistry , Lactones/chemistry , Molecular Structure , Oxidation-ReductionABSTRACT
An efficient synthesis of ent-halimanolide 2 (15,16-epoxy-12-oxo-ent-halima- 5(10),13(16),14-trien-18,2beta-olide), from ent-halimic acid has been achieved, corroborating the structure of the natural compound and establishing its absolute configuration.
Subject(s)
Diterpenes/chemical synthesis , Diterpenes/chemistry , Euphorbiaceae/chemistryABSTRACT
For the first time ent-labdanes have been synthetised starting from ent-halimic acid, following a route that is the reverse of the biosynthetic one leading to the former compounds.
Subject(s)
Diterpenes/chemistry , Diterpenes/chemical synthesis , Glycosides/chemical synthesis , Glycosides/chemistryABSTRACT
The rearrangement under oxidative conditions of 3-(benzyloxy)-tetrahydro- 2,6,6-trimethyl-2H-pyran-2-carbaldehydes to afford a chiral protected tetrahydrofuran lactol is described.