Ent-halimic Acid Research Articles

Halimanes and cancer: ent-halimic acid as a starting material for the synthesis of antitumor drugs.

The development of new anti-cancer agents is an urgent necessity nowadays, as it is one of the major causes of mortality worldwide. Many drugs currently used are derived from natural products. Halimanes are a class of bicyclic diterpenoids present in various plants and microorganisms. Many of them exhibit biological activities such as antitumor, antimicrobial, or anti-inflammatory. Among them, ent-halimic acid is an easily accessible compound, in large quantities, from the ethyl acetate extract of the plant Halimium viscosum, and it has been used as a starting material in a number of bioactive molecules. In this work, we review all the natural halimanes with antitumor and related activities until date as well as the synthesis of antitumor compounds using ent-halimic acid as a starting material.

The Methylene-Cycloalkylacetate (MCA) Scaffold in Terpenyl Compounds with Potential Pharmacological Activities

Recently, the methylene-cycloakylacetate (MCA) scaffold has been reported as a potential pharmacophore for neurite outgrowth activity. In this work, natural diterpenes that embed MCA fragments are reviewed, as they are major components of Halimium viscosum: ent-halimic acid, the prototype for these bioactive compounds. Herein, structures, sources, and activities for the natural diterpenes, as well as their synthetic derivatives of interest, are reviewed.

Synthesis and biological activity of polyalthenol and pentacyclindole analogues

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.

Synthesis of 12-epi-ent-polyalthenol an antitumour indole sesquiterpene alkaloid

The synthesis of 12-epi-ent-polyalthenol, 10, and its epimer at C-19, 11, from ent-halimic acid as starting material has been carried out. The structure of the natural product polyalthenol 1 is confirmed in this way. The synthesized indole sesquiterpenes 10 and 11 and their acetylderivatives 32 and 33 inhibited cellular proliferation of a number of human leukaemic and solid tumour cell lines.

Synthesis of quinone/hydroquinone sesquiterpenes

ent-Halimic acid has been used in the synthesis of the quinone/hydroquinone sesquiterpenes (−)-aureol, (−)-smenoqualone, (−)-neomamanuthaquinone and in the formal synthesis of (−)-cyclosmenospongine.

ChemInform Abstract: Diterpenic α- and β-Hydroxybutanolides with Antifeedant Activity: Semisynthesis and Absolute Configuration.

Abstract Two series of ent-halimanolides (15,16-olides and 16,15-olides), analogues of biologically active diterpene lactones, were synthesized starting from ent-halimic acid methyl ester. The absolute configuration was determined by CD spectroscopy and corroborated by X-ray analysis. Antifeedant testing has been carried out on these compounds.

Synthesis of an ent-Halimanolide from ent-Halimic Acid

An efficient synthesis of ent-halimanolide 2 (15,16-epoxy-12-oxo-ent-halima-5(10),13(16),14-trien-18,2β-olide), from ent-halimic acid has been achieved, corroborating the structure of the natural compound and establishing its absolute configuration.

Synthesis of (+)-Thiersindole C

The indole diterpene alkaloid (+)-thiersindole C has been synthesised from ENT-halimic acid. Firstly was elaborated the bi-cyclic system, secondly a Fischer indolization was used to obtain the north side chain and finally elongation of the south side chain was achieved with an isoprene unit. The synthesis of (+)-thiersindole C has corroborated the absolute configuration for the natural product (-)-thiersindole C. The synthesized (+)-thiersindole C showed antitumor activity against a number of human tumor cell lines with an IC 50 in the range of 10 -5 M.

Synthesis of novel antitumoural analogues of dysidiolide from ent-halimic acid

Several sesterterpenolides analogues of dysidiolide have been synthesized and their in vitro antitumoural activity against human HeLa, A549, HT-29 and HL-60 carcinoma cells is presented. The proliferation inhibition data showed a significant antitumour activity of the compounds 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5, inhibiting proliferation of distinct cancer cell types with an IC 50 in the low micromolar range.

Synthetic studies towards picrasane quassinoids

An advanced intermediate 40 with the ABC ring of the picrasane quassinoid skeleton has been synthesised from ent-halimic acid. The bicyclic system of the starting material has been incorporated as the BC part of the ABC system. Until date, no diterpenes of the antipode series have been used in this kind of approach.

Synthetic Studies Towards the ent-Labdane Diterpenoids: Rearrangement of ent-Halimanes

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.

Chemistry of ent-Halimic Acid: Synthesis of [4.3.3]Propellanes

ent-Halimic acid was used as the starting material for an efficient synthesis of a series of tetranor derivatives, functionalized at C-18. These compounds could be used to synthesise [4.3.3]propellanes, oxides and lactones similar to ambreinolide, all of which may be of interest to the perfume industry.

Synthesis of (+)‐Agelasine C. A Structural Revision.

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Synthesis of (+)-agelasine C. A structural revision

An efficient synthesis of (+)-agelasine C has been achieved from ent-halimic acid. The structure and absolute configuration of the natural product (−)-agelasine C was established and a structure for epi-agelasine C, is proposed.

Synthesis ofent-Halimanolides froment-Halimic Acid

Three natural ent-halimanolides have been synthesized from ent-halimic acid. Their structures have been confirmed as well as their absolute configurations established. Bestmann methodology has been used for the synthesis of butenolides and for the synthesis of γ-hydroxybutenolides the Boukouvalas method has been employed.

Synthesis of bioactive sesterterpenolides from ent-halimic acid. 15-epi-ent-Cladocoran A and B.

The bioactive sesterterpenoid gamma-hydroxybutenolides 15,18-bisepi-ent-Cladocoran A and B, 1 and 2, and 15-epi-ent-Cladocoran A and B, 57 and 55, were synthesized from ent-halimic acid. The synthesized sesterterpenolids 2, 55, 57, and 59 inhibited cellular proliferation (IC(50) congruent with 2 micro M) of a number of human leukaemic and solid tumor cell lines.

Synthesis and Absolute Configuration of (‐)‐Chettaphanin I and (‐)‐Chettaphanin II.

An efficient synthesis of chettaphanin I and II has been achieved from ent-halimic acid. The absolute configuration of the natural products was established by nOe experiment and by X-ray analysis of chettaphanin II.

Synthesis and absolute configuration of (−)-chettaphanin I and (−)-chettaphanin II

An efficient synthesis of chettaphanin I and II has been achieved from ent-halimic acid. The absolute configuration of the natural products was established by nOe experiment and by X-ray analysis of chettaphanin II.

Synthesis and absolute configuration of three natural ent-halimanolides with biological activity

The first three natural ent-halimanolides known until now have been synthesized from ent-halimic acid. Their structure have been confirmed as well as their absolute configurations established. Bestmann methodology has been used for the synthesis of butenolides and for the γ-hydroxybutenolides synthesis the Boukouvalas method has been employed. Biological testing has been carried out on these compounds.

Synthesis and absolute configuration of (−)-chettaphanin II

An efficient synthesis of chettaphanin II has been achieved from ent-halimic acid. The absolute configuration of the natural product was established and corroborated by X-ray analysis of chettaphanin II.