Metal-Free Activation of a C(sp)-H Bond of Aryl Acetylenes.

C(sp)-H Bond activation of acetylene molecule still remains a challenge for synthetic organic chemists. In practice, acetylenes are activated by strong bases and metals. The first example for activating acetylenic protons under base and metal-free conditions is reported here. It involves a general method for synthesizing propargylic derivatives of cotarnine. An array of tetrahydroisoquinolines alkaloids was synthesized by C(sp)-H bond activation of aromatic acetylenes with cotarnine at room temperature. A DFT-based mechanism is proposed for the reaction.

Palladium-catalyzed direct arylation of polysubstituted benzofurans.

An efficient access to 2-substituted 3-arylbenzofurans through a palladium-catalyzed C3 direct arylation of 2-substituted benzofurans with aryl bromides is described. The scope and limitation of this reaction was studied. The method tolerates a variety of functional groups on the aryl halide and has been successfully extended to polysubstituted benzofurans to obtain the corresponding 3-arylbenzofurans with good to excellent yields.

Synthesis of 3-aryl-2-arylamidobenzofurans based on the Curtius rearrangement.

The synthesis of novel 3-aryl-2-arylamidobenzofurans has been accomplished via a Curtius rearrangement strategy in four steps from benzofuran-2-carboxylic acids. The requisite Suzuki-Miyaura cross-coupling, with benzyl 3-bromobenzofuran-2-ylcarbamate or 2-arylamido-3-bromobenzofurans, revealed an unusual reductive debromination process due to the presence of the free NH group. This dehalogenation can be suppressed by N-alkylation. DMAP is an efficient reagent for the one-pot conversion of benzyl benzofuran-2-ylcarbamates into the corresponding benzofuran-2-arylamides through aroylation, thus acting both as an acyl transfer reagent and a deprotecting agent of the Cbz group. A mechanism is postulated.

Synthesis and biological study of a new series of 4'-demethylepipodophyllotoxin derivatives.

Etoposide (VP-16) is a potent human DNA topoisomerase II poison, derived from 4'-demethylepipodophyllotoxin, widely used in cancer chemotherapy. Continuous efforts have driven to synthesize new related compounds, presenting decreased toxic side effects, metabolic inactivation, drug resistance, and increased water solubility. Identified structure-activity relationships have pointed out the importance of the 4beta-substitution and of the configuration of the D ring. Here we report the synthesis of two novel series of derivatives of 4'-demethylepipodophyllotoxin. The first bears a carbamate chain in the 4 position (13a-f), whereas, in the second series, in addition to this chain, the lactone ring has been modified by shifting the carbonyl from position 13 to position 11 (27a-f). Moreover, an analogue of TOP-53 having this lactone modification has also been prepared (32). From this study, structure-activity relationships were established. Compounds 13a and 27a displayed potent cytotoxic activity against the L1210 cell line (10 to 20-fold higher than VP-16) and proved to be strong topoisomerase II poisons more potent than VP-16. From preliminary in vivo investigation of both compounds against P388 leukemia and orthotopically grafted human A549 lung carcinoma, it appeared that 13a and 27a constitute promising leads for a new class of antitumor agents.

Etoposide: discovery and medicinal chemistry.

Etoposide is an antitumor agent currently in clinical use for the treatment of small cell lung cancer, testicular cancer and lymphomas. Since the introduction of etoposide in 1971, its mechanism of action and potent antineoplastic activity has served as the impetus for intensive research activities in chemistry and biology. This drug acts by stabilizing a normally transient DNA-topoisomerase II complex, thus increasing the concentration of double-stranded DNA breaks. This phenomenon triggers mutagenic and cell death pathways. The function of topoisomerase II is understood in some detail, as is the mechanism of inhibition of etoposide at a molecular level. Etoposide has shortcomings of limited neoplastic activity against several solid tumors such as non-small cell lung cancer, cross-resistance to MDR tumor cell lines and low bioavailability. The design and synthesis of etoposide analogs is an activity of fundamental interest to the field of cancer chemotherapy. In the first part, this article is a survey of the discovery of etoposide, the DNA topoisomerase II structure and mechanism, and the models for drug-enzyme interaction. The last part is concerned with the search for new etoposide analogs based upon an empirical design.

Synthesis of aryl phosphates based on pyrimidine and triazine scaffolds.

The syntheses of the triazinyl-based bis-aryl phosphates 2 and 3, and of the aminopyrimidyl-based aryl phosphate 4 are described. Each compound contains a diaryl ether-phosphate structural motif. The synthetic route to bis-aryl phosphates 2 and 3 consisted in two nucleophilic substitution reactions with amines from cyanuric chloride, followed by a Suzuki coupling with the resulting 2,4-diamino-6-chloro-1,3,5-triazine derivative 12 to introduce the diaryl ether functionality. Aryl phosphate 4 was obtained via condensation of aryl guanidine 34 with aryloxyphenyl butenone 31. These de novo-designed aryl phosphates were evaluated as potential inhibitors of the Grb2-SH2 domain using an ELISA assay. The water-soluble sodium salt 26 of 3 gave an IC(50) value in the high micromolar range. Molecular modeling studies were subsequently performed upon modifying the 1,3,5-trisubstituted triazine scaffold of 3. Non-phosphate derivatives encompassing cyclopropane, pyrrole, keto-acid, and IZD fragments were thus step-wise designed and their Grb2-SH2 complexes were modeled by molecular dynamics. Some derivatives gave rise to an enriched pattern of H-bonds and cation-pi interactions with Grb2-SH2.

Synthesis and antiproliferative activity of retroetoposide.

Retro-4'-demethyl-4-epipodophyllotoxin 6 was synthesized in eight steps and 10% overall yield from 4'-demethyl-4-epipodophyllotoxin 12. Subsequent coupling of 22 with 1-O-trimethylsilyl-4,6-O-ethylidene-beta-D-glucoside 26 afforded retroetoposide 5 which is 10-fold less cytotoxic than etoposide against L1210 cell line.

Hemi-synthesis and biological activity of new analogues of podophyllotoxin.

Various 4-analogues of podophyllotoxin and epipodophyllotoxin were obtained via the formation of the corresponding 4-keto derivatives. Methyloximation of podophyllotoxone, followed by subsequent catalytic hydrogenation, gave stereoselective access to 4-alpha-amino-4-deoxypodophyllotoxin and from there, to the corresponding acetamido and formamido derivatives. Base-catalyzed isomerisation of 4-alpha-amino-4-deoxypodophyllotoxin led to the corresponding picropodophyllin isomer while the 4-beta-amino afforded a neopodophyllotoxin-like derivative. On the other hand, oxirane and hydroxymethyl-containing analogues were prepared from podophyllotoxin and 4-epi-4'-demethyl-podophyllotoxin, using a Takai olefination strategy. In the latter series, carboxaldehyde- and carboxylic acid-containing derivatives were also synthesized.