The drug market is still dominated by small molecules, and more than 80% of the clinical development of drug candidates in the top 20 pharmaceutical firms is still based on small molecules. The high cost of developing and manufacturing "biological drugs" will contribute to leaving an open space for drugs based on cheap small molecules. Four main routes can be explored to design affordable and efficient drugs: (i) a drastic reduction of the production costs of biological drugs, (ii) a real improvement of drug discovery via "computer-assisted combinatorial methods", (iii) going back to an extensive exploration of natural products as drug sources, and (iv) drug discovery by rational drug design and bio-inspired design that hopefully includes serendipity and human inspiration. At the border between bio-inspired design and rational design, one can imagine preparation of hybrid molecules with a dual mode of action to create efficient new drugs. In this Account, hybrid molecules are defined as chemical entities with two or more structural domains having different biological functions and dual activity, indicating that a hybrid molecule acts as two distinct pharmacophores. In order to obtain new antimalarial drugs that are affordable and able to avoid the emergence of resistant strains, we developed hybrid molecules with a dual mode of action (a "double-edged sword") able to kill multiresistant strains by oral administration. These hybrid molecules, named trioxaquines, with two pharmacophores able to interact with the heme target are made with a trioxane motif covalently linked to an aminoquinoline entity. More than 100 trioxaquines have been prepared by Palumed over a period of 4 years, and in collaboration with Sanofi-Aventis, the trioxaquine PA1103-SAR116242 has been selected in January 2007 as candidate for preclinical development.
This review article focuses on the molecular aspects of DNA cleavage by synthetic chemical nucleases (transition metal complexes endowed with redox properties and DNA affinity) and natural drugs (cytotoxic agents such as bleomycins or enediynes) . Unlike deoxyribonucleases, which catalyze the nucleophilic attack of water on the phosphorus atom of a particular phosphodiester entity, these nonhydrolytic DNA-cleavers are able to oxidize the sugar units, generally by hydrogen atom abstraction. Examples of oxidative attack on each of the five different C-H bonds of deoxyribose are known, depending on the nature, structure, type of activation, or mode of DNA interaction of the DNA-cleaver. Further evolution at the site of the initial lesion leads to the release of bases, oxidized deoxyribose units, or oxidized sugar fragments appended to the base or the terminal phosphate. In most cases the loss of a part (at least) of a nucleoside, with the concomitant loss of one base information, primarily induces the cleavage of the DNA strand. For both types of DNA cleavage reagents studied within the two last decades, the modes of activation and DNA binding are presented, as well as the details on the mechanism of deoxyribose oxidative degration. Because of the need for highly efficient and highly specific reagents, the development of new artificial and selective D N A cleavers, supported by an improved knowledge of these different mechanisms of DNA cleavage, is to-day a challenging area in the rational design of antitumoral or antiviral agents. as well as in the field of molecular biology.
In the present review, we report the discovery of the formation of esters and lactones by oxidation of ketones with a peroxide derivative, namely the Baeyer–Villiger reaction. This reaction was first reported by Adolf von Baeyer and Victor Villiger a century ago in 1899, just one year after the oxidant they used (KHSO5) has been described. Furthermore, Baeyer and Villiger established the composition of this new inorganic peroxide and showed that its instability was the reason of a controversy between several European chemists between 1878 and 1893. For the first 50 years the mechanism of the Baeyer–Villiger reaction was a matter of debate. A side product, 1,2,4,5‐tetraoxocyclohexane, was ruled out as an intermediate in the ester formation by Dilthey. Criegee postulated a nucleophilic attack of the oxidant on the carbonyl group. This mechanism was confirmed by von E. Doering by a labeling experiment with [18O]benzophenone. The rearrangement step occurs with retention of the stereochemistry at the migrating center. The competitive migration and the rate‐determining step are also discussed in this review.
Reported studies indicate that the association of potassium monopersulfate with [Mn(TMPyP)](OAc)5, a water-soluble manganese porphyrin complex, leads to an efficient reagent for the oxidative cleavage of DNA. Single-strand breaks (SSBs) are observed on double-stranded DNA at manganese porphyrin concentrations as low as 0.5 nM with a short incubation time of 1 min. The number of SSBs linearly varies with the concentration of the manganese complex, and potassium monopersulfate is at least 3 orders of magnitude more efficient as oxygen source than hydrogen peroxide. Cleavage efficiency is optimal in the pH range 7.5-9.0 for a NaCl concentration between 80 and 150 mM or for a MgCl2 concentration of 10 mM. At very low manganese porphyrin concentration and by increasing the incubation time a catalytic cleavage activity of the complex is evidenced: up to 5 SSBs per manganese porphyrin are observed. The high cleavage activity of the monopersulfate-manganese porphyrin system makes it a good candidate for DNA-footprinting experiments.
This large multicenter study provides strong evidence that SEAL adversely impacts cancer prognosis. The mechanism through which SEAL increases local recurrence is an important area for future research.
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