Visible Light Promoted Site-Specific Functionalization of α-Acyloxy Carboxamides: Unlocking a Forbidden Chemical Space in the Passerini Reaction.

The facile generation of the α-acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a 4-formyl-1,4-dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini-derived products not previously amenable to direct aldehyde-based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating "impossible" aldehydes.

Photocatalytic Radical Coupling of Organoborates with α-Halogenated Electron-Poor Olefins.

Herein, we report the visible-light-mediated addition of organoborates to α-halogenated electron-poor olefins enabled by an environmentally benign metal-free catalyst. The method accommodates a variety of boronic acid derivatives as well as alkenes and delivers the corresponding saturated α-halo-derivatives in up to 90% yields. The obtained products are high-value building blocks in organic synthesis, allowing for a variety of follow-up transformations.

Stereoselective synthesis of 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as PIM kinase inhibitors inspired from marine alkaloids.

We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein.

Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.

MutT Homolog 1 (MTH1): The Silencing of a Target.

MTH1 is a member of the nudix phosphohydrolase superfamily of enzymes, and it is involved in nucleotide pool homeostasis. The protein exerts its scavenging action by hydrolyzing oxidized nucleotides, thus avoiding their misincorporation into replicating DNA. Recent reports have validated its inhibition as a potential broad-spectrum target in oncology and have described small molecules able to engage this target with antiproliferative effect.

Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by).

Insights into PARP Inhibitors' Selectivity Using Fluorescence Polarization and Surface Plasmon Resonance Binding Assays.

PARP inhibitors are an exciting new class of antineoplastic drugs that have been proven to be efficacious as single agents in cancer settings with inherent DNA repair defects, as well as in combination with DNA-damaging chemotherapeutics. Currently, they are designed to target the catalytic domain of PARP-1, the most studied member of the family, with a key role in the DNA-damage repair process. Because PARP inhibitors are substrate (NAD(+)) competitors, there is a need for a deeper understanding of their cross-reactivity.

Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family.

Italian chemists' contributions to named reactions in organic synthesis: an historical perspective.

From the second half of the 19th century up to modern times, the tremendous contribution of Italian chemists to the development of science resulted in the discovery of a number of innovative chemical transformations. These reactions were subsequently christened according to their inventors' name and so entered into the organic chemistry portfolio of "named organic reactions". As these discoveries were being conceived, massive social, political and geographical changes in these chemists' homeland were also occurring.

PARP inhibitors in cancer therapy: an update.

Introduction: Inhibitors of the poly(ADP-ribose) polymerases (PARPs) family of proteins are currently being evaluated as potential anticancer medicines at both preclinical and clinical levels. They have the peculiarity to increase the efficacy of DNA-damaging agents and to selectively target tumor cells with specific DNA repair defects. This later development of these drugs should make it possible, in principle, to selectively target neoplastic vs healthy cells, thus realizing the Ehrlich's magic bullet concept of a personalized and tailored cure of diseases.

A submarine journey: the pyrrole-imidazole alkaloids.

In his most celebrated tale "The Picture of Dorian Gray", Oscar Wilde stated that "those who go beneath the surface do so at their peril". This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity--from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters.

Poly(ADP-ribose) polymerase inhibition in cancer therapy: are we close to maturity?

Background: During the last few years an increasing number of poly(ADP-ribose) polymerase (PARP) inhibitors have been appearing in the context of cancer therapy. This is mainly due to a better knowledge of the best-characterized member of the PARP family of enzymes, PARP-1, further reinforced by the recognition of the clinical benefits arising from its inhibition.

Objective/method: The aim of this review is to give the reader an update on PARP inhibition in cancer therapy, by covering both the scientific (SciFinder) search) and the patent literature (Chemical Abstract/Derwent search) published recently (2005-2008).

A straightforward total synthesis of (-)-chaetominine.

A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available D-tryptophan methyl ester, based on a short and straightforward (nine steps) sequence. The early stage introduction (first step) of the quinazolinone moiety and the late stage introduction (penultimate step) of the hydroxy group allowed a synthetic strategy devoid of protective groups.

Improved synthesis of polyfluorinated L-lysine for 19F NMR-based screening.

Polyfluorinated N-alpha-Fmoc-is an element of-Boc-L-lysine represents the best-in-class among a set of polyfluorinated amino acids (PFAs) which are useful tools for (19)F NMR-Based Screening. In this communication, optimized reaction conditions that allowed for the multi-gram preparation of this unnatural amino acid are reported.

Polyfluorinated amino acids for sensitive 19F NMR-based screening and kinetic measurements.

Two novel series of polyfluorinated amino acids (PFAs) were designed and synthesized according to a very short and scalable synthetic sequence. The advantages and limitations of these moieties for screening purposes are presented and discussed. The potential applications of these PFAs were tested with their incorporation into small arginine-containing peptides that represent suitable substrates for the enzyme trypsin.

A new glycociamidine ring precursor: syntheses of (Z)-hymenialdisine, (Z)-2-debromohymenialdisine, and (+/-)-endo-2-debromohymenialdisine.

[chemical reaction: see text]. The synthesis of the C11H5 marine sponge alkaloids, (Z)-hymenialdisine and (Z)-2-debromohymenialdisine, is described. A key step was the condensation between aldisine or its monobromo derivative and a new, efficient imidazolinone-based glycociamidine precursor.

Sensitivity improvement in 19F NMR-based screening experiments: theoretical considerations and experimental applications.

NMR-based binding and functional screening performed with FAXS (fluorine chemical shift anisotropy and exchange for screening) and 3-FABS (three fluorine atoms for biochemical screening) represents a potential alternative approach to high-throughput screening for the identification of novel potential drug candidates. The major limitation of this method in its current status is its intrinsic low sensitivity that limits the number of tested compounds. One approach for overcoming this problem is the use of a cryogenically cooled (19)F probe that reduces the thermal noise in the receiver circuitry.

Synthesis of 3 10-helix-inducing constrained analogues of L-proline.

A bicyclic indolizidinone carboxylic acid and a tricyclic constrained analogue of l-proline were synthesized and evaluated for their ability to induce helix formation as l-Ala tetrapeptides. Variable-temperature NMR, DMSO titration, CD spectra, and X-ray structure analyses, in conjunction with molecular modeling, confirmed the existence of 3(10)-helical motifs with di- and tetrapeptides of l-Ala.

Synthesis of functionally diverse and conformationally constrained polycyclic analogues of proline and prolinol.

Alkylation of the monoenolate of N-Boc-l-pyroglutamic acid methyl ester with a variety of benzylic halides and their homologues gave the corresponding anti-C-4-alkylated products as major products. Formation of the N-Boc-iminium ion and Friedel-Crafts intramolecular cationic ring closure afforded a series of fused 1-azacyclodihydroindene derivatives with interesting topologies. Functional diversity was introduced via further manipulation of pendant groups on the original proline motif as well as on the aromatic moiety.