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.

Antibacterial Natural Halimanes: Potential Source of Novel Antibiofilm Agents.

The development of new agents against bacteria is an urgent necessity for human beings. The structured colony of bacterial cells, called the biofilm, is used to defend themselves from biocide attacks. For this reason, it is necessary to know their structures, develop new agents to eliminate them and to develop new procedures that allow an early diagnosis, by using biomarkers. Among natural products, some derivatives of diterpenes with halimane skeleton show antibacterial activity. Some halimanes have been isolated from marine organisms, structurally related with halimanes isolated from Mycobacterium tuberculosis. These halimanes are being evaluated as virulence factors and as tuberculosis biomarkers, this disease being one of the major causes of mortality and morbidity. In this work, the antibacterial halimanes will be reviewed, with their structural characteristics, activities, sources and the synthesis known until now.

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.

Organocatalyzed Synthesis of [3.2.1] Bicyclooctanes.

Organocatalysis constitutes one of the main research areas in organic chemistry from the last two decades. This chemistry has been applied to the synthesis of many natural products and structures in a manner that reduces the residues and so the ecological impact. In this review, we consider the work that has been done for the synthesis of bicyclo[3.2.1]octane framework. This structure is present in many natural products with very important biological activities.

Halimane diterpenoids: sources, structures, nomenclature and biological activities.

Covering: 1970 to 2017 Diterpenes with a halimane skeleton constitute a small group of natural products that can be biogenetically considered as being between labdane and clerodane diterpenoids. Some of these compounds show biological activities, such as antitumour, mosquito repellency, germination inhibition and antimicrobial, as well as being biomarkers for tuberculosis. To the best of our knowledge, there are no reviews on these compounds. In this review, halimane skeleton diterpenoids are classified according to their biogenetic origin, characterization and/or the enzymes involved in their biosynthesis. Herein, a review of their synthesis or synthetic approaches is communicated.

Diastereoselective synthesis of chiral 1,3-cyclohexadienals.

A novel approach to the production of chiral 1,3-cyclohexadienals has been developed. The organocatalysed asymmetric reaction of different ß-disubstituted-α,ß-unsaturated aldehydes with a chiral α,ß-unsaturated aldehyde in the presence of a Jørgensen-Hayashi organocatalyst provides easy and stereocontrolled access to the cyclohexadienal backbone. This method allows for the synthesis of potential photoprotective chiral 1,3-cyclohexadienals and extra extended conjugation compounds in a simple manner.

Highly Functionalized Ring B Labdane Synthesis as Key Intermediate in the Route to Forskolin.

Sclareol has been employed as starting material for the synthesis of several advanced intermediates towards the synthesis of highly ring B oxygenated labdanes. Dinorlabdanes 6,7,8,9-tetraoxygenated with 6,7-dioxygenated functionalities with a-cis or O-cis dispositions, have been prepared and can be used for forskolin or analogues synthesis.

Ring-closing metathesis as key step in the synthesis of Luffarin I, 16-epi-Luffarin I and Luffarin A.

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.

Synthesis of Luffarin L and 16-epi-Luffarin L Using a Temporary Silicon-Tethered Ring-Closing Metathesis Reaction.

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.

Synthesis and bioactivity of Luffarin I.

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.

Enantioselective synthesis of cis-decalins using organocatalysis and sulfonyl Nazarov reagents.

The first organocatalytic synthesis of cis-decalins using sulfonyl Nazarov reagents is reported. The Jørgensen's catalyst directs this highly enantioselective synthesis using different cyclohexenal derivatives.

Biomimetic synthesis of two salmahyrtisanes: salmahyrtisol A and hippospongide A.

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.

Synthesis of Bioconjugate Sesterterpenoids with Phospholipids and Polyunsaturated Fatty Acids.

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.

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.

Sesquiterpenyl indoles.

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.

Domino elimination/nucleophilic addition in the synthesis of chiral pyrrolidines.

Polyhydroxylated pyrrolidines have been synthesized in a one-pot procedure by the addition of an organometallic reagent to isoxazolidines obtained by a 1,3-dipolar cycloaddition between nitrones and vinylsulfones. This method highlights sulfone reactivity and provides an easy approach for the preparation of chiral pyrrolidines using cyclic imines as key intermediates.

Synthesis of a new chiral pyrrolidine.

The synthesis of a new chiral pyrrolidine has been performed using 2,3-O-isopropylidene-D-erythronolactol as a suitable starting material.

Yamaguchi-type lactonization as a key step in the synthesis of marine metabolites: (+)-luffalactone.

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.

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-18,2beta-olide), from ent-halimic acid has been achieved, corroborating the structure of the natural compound and establishing its absolute configuration.

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.