Simple and efficient synthesis of various dibenzofuran carbaldehydes

We herein report simple and efficient methods for the synthesis of various formyl derivatives of dibenzofuran. The aldehydes reported are prepared in at most three steps and in yields greater than 60% from commercially available dibenzofuran, with one exception where isomers must be separated. The protocols described involve either formylation of previously functionalized dibenzofuran derivatives or the initial introduction of the formyl group and subsequent further functionalization under standard reaction conditions as described. We have also reported an efficient and simple method for the synthesis of key methoxydibenzofurans in high yield (65% overall for two steps)CONICYT (Chile) through FONDECYT 315047

A New, One-Pot, Three-Component, Solvent-Free Synthesis of Amidoalkyl Dibenzofuranols and Dibenzofuran-Condensed 1,3-Oxazin-3-ones

10.1055/s-0029-1218624Synthesis201006959-96

A Multiaction and Multitarget Ru(II)-Pt(IV) Conjugate Combining Cancer Activated Chemotherapy and Photodynamic Therapy to Overcome Drug Resistant Cancers

International audienceCancer has emerged as one of the deadliest diseases worldwide. Pt(II) complexes are commonly used to treat this condition. To reduce their side effects and improve their pharmacological properties, Pt(IV) complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, photodynamic therapy (PDT) has received increasing attention over the last years. Among other compounds studied as photosensitizers (PSs), Ru(II) polypyridine complexes have gained much attention over the recent years due to their attractive characteristics. In this article, the first example of a novel Pt(IV)-Ru(II) conjugate, which combines cancer activated chemotherapy with photodynamic therapy, is presented. Upon entering the cancer cell, the Pt(IV) centre is reduced to Pt(II) and the axial ligands including the Ru(II) complex and phenylbutyrate are released. As each component has its individual target, the conjugate exerts a multitarget and multiaction effect with (photo-)cytotoxicity values upon irradiation up to clinically relevant 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids

Expanding the Arsenal of PtIV Anticancer Agents: Multi-action PtIV Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group

Most multi-action PtIV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general approach for synthesis of PtIV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the PtIV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO2, rapidly generating the active drugs. In contrast, succinate-linked drugs did not readily release the free drugs. The carbonate-bridged ctc-[Pt(NH3)2(PhB)(Gem-Carb)Cl2] was significantly more cytotoxic than the succinate-bridged ctc-[Pt(NH3)2(PhB)(Gem-Suc)Cl2], and more potent and less toxic than gemcitabine, cisplatin, and co-administration of cisplatin and gemcitabine

Dibenzofuranylethylamines as 5-HT2A/2C receptor agonists

The human 5-HT2 receptor subtypes have high sequence identity in their orthosteric ligand-binding domain, and many agonists are poorly selective between the S-HT(2A )and 5-HT2C subtypes. Nevertheless, their activation is associated with different pharmacological outcomes. We synthesized five phenethylamine analogs in which the benzene ring is replaced by a bulky dibenzo[b,d]furan moiety and found a couple with >70-fold 5-HT2C selectivity. Molecular docking studies of the most potent compound (5) at both receptor subtypes revealed the likely structural basis of its selectivity. Although in both cases, some crucial interactions are conserved, the change of the Ala222(5.46) residue in the 5-HT2C receptor to the larger Ser242(5.46 )in the 5-HT2A subtype, which is the only structural difference between the orthosteric binding pockets of both receptors, weakens a pi-pi stacking interaction between the dibenzofuran moiety and the important Phe(6.52) residue and breaks a hydrogen bond between the dibenzofuran oxygen and Ser(5.43) explaining the selectivity of compound 5 for the 5-HT(2C )receptor. We believe that this effect of the residue at position 5.46 merits further exploration in the search for selective 5-HT2C receptor agonists that are of considerable interest in the treatment of schizophrenia and substance abuse.Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), CONICYT FONDECYT: 1171484, 315047