Ángel M. Montaña

The rational design of anticancer platinum complexes: the importance of the structure-activity relationship.

The ideal drug discovery process of new platinum based drugs should take into account three basic fundaments: on one side the mechanisms of action and the corresponding target biomolecules, on the other side, the possible mechanisms of resistance of cancer cells and their biochemical pathways and, finally, the pharmacokinetic and toxicity properties (ADMET) that will condition the clinical usefulness of the new drugs. At the end of this rational process always we face the necessity to design a molecule with a structure and certain physical and chemical properties. The structure is then a key fundamental issue when thinking of new anticancer platinum compounds. When analyzing the influence of molecular structure on anticancer activity it is useful to make the dissection of platinum complexes into different significant subunits or moieties, of the molecular structure. Thus, the following structural and electron dependent parameters are important to facilitate the comparison among platinum complexes: a) Nature of the non-labile ligand or carrier ligand (NLG); b) Nature of the labile ligand or leaving group (LG); c) Oxidation state of platinum atom; d) Type of atoms (connecting atoms X, Y, Z, W) that link ligands to platinum atom; e) Nature of the axial groups (AG) in platinum(IV) complexes; f) Nuclearity or number of Pt atoms in the platinum complexes; g) Formal charges present in the molecule and h) Intrinsic bioactivity of some ligands or bioactivity induced by molecules attached to ligands by linkers (in order to get a double mechanism of action or a parallel biological activity).

Enantioselective Synthetic Methodology to Prepare trans-Fused Bicyclo[5.3.0]decane Systems: an Approach to the Synthesis of the Pseudoguaiane Carbon Framework

Abstract An enantioselective method to prepare trans-fused bicyclo[5.3.0]decane systems is described. This methodology is based on two key reactions: a [4+3] cycloaddition reaction (to generate the seven-membered ring) and the Nicholas reaction (to insert the five-membered ring). The application of this methodology to the enantioselective synthesis of the pseudoguaiane carbon skeleton is presented. This enantioselective strategy for construction of the trans-fused bicyclo[5.3.0]decane system is versatile and could be applied to the preparation of a wide range of bioactive natural products containing that carbon framework.

Enantioselective synthesis of trans-fused bicyclo[5.3.0]decane systems via a tandem [4+3] cycloaddition-Nicholás reaction

An enantioselective synthetic methodology to prepare trans-fused bicyclo[5.3.0]decane systems is presented. It is a very versatile methodology based on two key reactions: [4+3] cycloaddition reaction (to generate the seven-membered ring) and the Nicholas reaction (that facilitates the insertion of the five-membered ring). This methodology allows the easy preparation of a wide range of bioactive natural products containing the trans-fused bicyclo[5.3.0]decane system. The application of this methodology to the enantioselective synthetic approach to the pseudoguaiane carbon-skeleton is described.

2-Functionalized furans as precursors of versatile cycloheptane synthons

Abstract An study on the influence of steric and electronic effects of a function attached at C-2 of furans in the yield and diastereoselectivity of [4 + 3] cycloaddition reactions with oxyallyl cations is presented. In almost all studied furans a cis diastereospecificity and a high endo diastereoselectivity is observed. Increasing bulkyness of the function attached at C-2 of furans, the endo diastereoselectivity increases, but yield decreases. Increasing the electronic density of the furan system, by an electron donating group at C-2, both yield and diastereoselectivity increase.

New methodology for the [4+3] cycloaddition reactions: generation of oxyallyl cations from α,α′-diiodoketones under sonochemical or thermal conditions

A new methodology to perform [4+3] cycloaddition reactions of suitable dienes and 1,3-dimethyl-2-oxyallyl cations is presented. The reaction is carried out starting from commercially available dienes and easy-handling α,α′-diiodoketones, which are reduced by the Zn/Cu couple to generate the oxyallyl cation as intermediate. The reaction is carried out under mild thermal or sonochemical conditions at low temperatures (from 0 to −44°C) and for short reaction times (<15 min). This methodology represents a good alternative respect to the actual procedures based on other reducing agents or starting from more elaborate precursors of the oxyallyl cations.

Induction of asymmetry on the [4+3] cycloaddition reaction of C2-functionalized furans

A study of the induction of asymmetry on the [4+3] cycloaddition reaction of some 13 C2-substituted furan derivatives with 2-oxyallyl cation is presented. The asymmetry was induced by a chiral auxiliary on C2 of furan. A cis diastereospecificity and a high endo diastereoselectivity are observed in almost all studied cases. On decreasing the distance between the stereocenter of the chiral auxiliary and the reactive C2-carbon of the furan ring, the π-facial diastereoselectivity is increased, especially by using chiral furyl-sulfoxides.

New synthetic methodology to prepare polyfunctionalized heptane building blocks with four stereocenters: synthesis of the (±)-C17–C23 subunit of Ionomycin

A new synthetic methodology for preparing polyfunctionalized heptane building blocks with up to four stereocenters has been developed. 2,4-Dimethyl-1-methoxy-8-oxabicyclo-[3.2.1]-oct-6-en-3-one has been used as precursor, which can be easily prepared by a [4+3] cycloaddition reaction between 2-methoxy-furan and the oxyallyl cation generated in situ from 2,4-dibromo-3-pentanone. The cycloadducts have an acetal functionality on C1 which allows easy opening of the oxabicyclic system, affording versatile synthons. The application of this methodology to the synthesis of the C17–C23 subunit of Ionomycin is presented.

Synthesis of the C17–C23 subunit of Ionomycin from C1-functionalized 8-oxabicyclo[3.2.1]oct-6-en-3-one. New synthetic methodology to prepare polyfunctionalized heptane building blocks with four stereocenters

Abstract The application of a new methodology to synthesize the C17–C23 subunit of Ionomycin is presented. This synthetic methodology is based on the preparation of heptane building blocks with four stereocenters and up to four different organic functionalities. 2,4-Dimethyl-1-methoxy-8-oxabicyclo[3.2.1]oct-6-en-3-one has been used as a key intermediate, which can easily be prepared by a [4+3] cycloaddition reaction between 2-methoxy-furan and the oxyallyl cation generated in situ from 2,4-dibromo-3-pentanone. This cycloadduct has an acetal functionality on C1 which allows the easy opening of the oxabicyclic system, affording versatile synthons.

Synthesis, DNA interaction and cytotoxicity studies of cis-{[1, 2-bis(aminomethyl)cyclohexane]dihalo}platinum(II) complexes.

A series of platinum compounds with an analogue structure to cisplatin have been synthesized and their biological activity against HL-60 cancer cell line has been studied. The interaction with DNA was evaluated by circular dichroism (CD), electrophoresis and atomic force microscopy (AFM) techniques showing slight but significant structure-dependent differences among the evaluated complexes. The cytotoxicity assays afforded interesting relationships between the structure and the biological activity, thus, a better antiproliferative activity was observed for the complexes with higher hydrophobicity: the methoxylated complexes showed better activity than the hydroxylated ones (17versus20 and 19versus21). Especially compound 22 having a fatty acid subunit presented a promising cytotoxic activity. On the other hand, dichloro complexes 12 and 13 had better activities than the diiodo complexes, probably due to their better metabolic stability. Between both dichloro complexes the aromatic one showed much higher activity, which could be rationalized on the basis of the intercalating ability of the benzene ring. The flow cytometry assays indicated that most of the complexes induced the cell death by apoptosis except for aromatic compound 12 and the lipophilic compound 22 that induced preferably a mechanism of necrosis.

General method of assignment of relative stereochemistry in C‐1‐substituted 2,4‐dimethyl‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐one by 1H and 13C NMR correlations

The 1H and 13C NMR spectra of cis‐endo (a) and cis‐exo (b) diastereoisomeric pairs of five differently C‐1‐functionalized 2,4‐dimethyl‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐ones were completely assigned. Several trends regarding the variation of chemical shifts and coupling constants of hydrogen and carbon atoms, on changing the configuration at C‐2 and C‐4 in both diastereoisomers, were observed by correlation of spectral data: methyl groups attached at C‐2 and C‐4 in a appear in 1H NMR at higher field than in diastereoisomer b. Simultaneously, H‐2 and H‐4 result in a lower field in a than in b. Both effects are due to the different interactions of hydrogens H‐2, H‐4, H‐9 and H‐10 with the bridging oxygen. In 13C NMR spectra it is possible to observe an upfield shift of C‐9, C‐10 and C‐3 in b versus a. The difference observed in chemical shifts of the aforementioned hydrogens and carbons, between both diastereoisomers, allows one to assign the configuration at C‐2 and C‐4 in such structures. This phenomenon has wide scope and validity and could be applied to the stereochemical determination of any pair of diastereoisomers (a and b), independently of the function attached to C‐1 of the oxabicyclic system. ©1998 John Wiley & Sons, Ltd.