The freely accessible web resource PASS Online is presented. This resource is designed for the prediction of the biological activity spectra of organic compounds based on their structural formulas for more than 4000 types of biological activity with average accuracy above 95% (
 http://www.way2drug.com/passonline
 ). The prediction is based on an analysis of the structure-activity relationships in the training set containing information on the structure and biological activity of more than 300000 organic compounds. The possibilities and limitations of this approach are described. Recommendations are given for interpreting the prediction results. Examples are given for the practical use of the PASS Online web resource in order to establish priorities for chemical synthesis and biological testing of substances on the basis of prediction results. The further trends are considered for the using PASS Online as an Internet platform for joint projects of academic researchers for the search and development of new pharmaceutical agents.

https://link.springer.com/content/pdf/10.1007%2Fs10593-014-1496-1.pdf

Prediction of the Biological Activity Spectra of Organic Compounds Using the Pass Online Web Resource

Multicomponent reactions (MCRs) are composed of three or more reagents in which the final product has all or most of the carbon atoms from its starting materials. These reactions represent, in the medicinal chemistry context, great potential in the research for new bioactive compounds, since their products can present great structural complexity. The aim of this review is to present the main multicomponent reactions since the original report by Strecker in 1850 from nowadays, covering their evolution, highlighting their significance in the discovery of new bioactive compounds. The use of MCRs is, indeed, a growing field of interest in the synthesis of bioactive compounds and approved drugs, with several examples of commerciallyavailable drugs that are (or can be) obtained through these protocols.

Multicomponent Reactions for the Synthesis of Bioactive Compounds: A Review

2-Alkynylbenzamides underwent different reaction pathways when allowed to react under PdI2-catalyzed oxidative carbonylation conditions, depending on the nature of the external nucleophile and reaction conditions. Thus, oxidative carbonylation of 2-ethynylbenzamides, bearing a terminal triple bond, carried out in the presence of a secondary amine as external nucleophile, selectively led to the formation of 3-[(dialkylcarbamoyl)methylene]isoindolin-1-ones through the intermediate formation of the corresponding 2-ynamide derivatives followed by intramolecular nucleophilic attack by the nitrogen of the benzamide moiety on the conjugated triple bond. On the other hand, 3-[(alkoxycarbonyl)methylene]isobenzofuran-1(3H)imines were selectively obtained when the oxidative carbonylation of 2-alkynylbenzamides, bearing a terminal or an internal triple bond, was carried out in the presence of an alcohol R′OH (such as methanol or ethanol) as the external nucleophile and HC(OR′)3 as a dehydrating agent, necessary to av...

Divergent palladium iodide catalyzed multicomponent carbonylative approaches to functionalized isoindolinone and isobenzofuranimine derivatives.

This review is the sixth update of the original article published in 1999 on the application of MALDI mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2010. General aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, arrays and fragmentation are covered in the first part of the review and applications to various structural typed constitutes the remainder. The main groups of compound that are discussed in this section are oligo and polysaccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals. Many of these applications are presented in tabular form. Also discussed are medical and industrial applications of the technique, studies of enzyme reactions and applications to chemical synthesis.

/pdf/analysis-of-carbohydrates-and-glycoconjugates-by-matrix-52w3ihqvq6.pdf

Analysis of carbohydrates and glycoconjugates by matrix-assisted laser desorption/ionization mass spectrometry: an update for 2009-2010.

A variety of 4H-chromenes, benzochromenes, 4,5-dihydropyrano[3,2-c]chromenes, 4H-pyran-3-carboxylates, and 3,4-disubstituted isoxazol-5(4H)-ones have been synthesized in high yields by using potassium hydrogen phthalate (KHP) as an inexpensive, commercially available catalyst. It was found that the three-component tandem reaction enabled synthesis of pyran-annulated heterocycles in water at 50 °C. 3,4-Disubstituted isoxazol-5(4H)-ones were synthesized by use of 10 mol% KHP in water at room temperature. Also, treatment of methylene-containing compounds (malononitrile or ethyl cyanoacetate) with aromatic aldehydes in the presence of 5 mol% KHP resulted in α,β-unsaturated nitriles. The procedure is an easily performed, straightforward method for synthesis of a variety of pyran-annulated compounds, isoxazol-5(4H)-one-containing heterocycles, and Knoevenagel adducts. The reaction is safe, uses mild conditions, and is environmentally benign. Other notable advantages are reuse of the catalyst, no use of hazardous organic solvents, and ease of work-up.

Efficient tandem synthesis of a variety of pyran-annulated heterocycles, 3,4-disubstituted isoxazol-5(4H)-ones, and α,β-unsaturated nitriles catalyzed by potassium hydrogen phthalate in water

Carbodiimide that was generated from the condensation reaction of iminophosphorane with phenylisocyanate was allowed to react with different phosphorus nucleophiles. Thus, the in situ resulted heterocumulene reacted with dialkylhydrogenphosphonates in tetrahydrofuran (THF)/FeCl(3) /H(2) O system to give fused pyrrole- (≈14%) and pyrimidinephosphonates (≈57%). On the other hand, with tris-(dialkyl)aminophosphines, the reaction afforded the corresponding hexaalkylphosphinic diamides as a water-sensitive fine powder, quite stable for a few days in a desiccator. When a protonating agent was present in the reaction medium, the reaction was markedly accelerated leading to the formation of the phosphamides. Next, some saturated and unsaturated Horner-Emmons reagents were applied in situ to the same carbodiimide to obtain more phosphorylated N-heterocycles. The analgesic and antiinflammatory activities of the newly synthesized compounds were investigated and showed significant activities. Finally, we further estimated the antitumor activity of five new phosphonates against four carcinoma cell lines.

Carbodiimides in the synthesis of enamino- and α-aminophosphonates as peptidomimetics of analgesic/antiinflammatory and anticancer agents.

Design of new arylamino-2-ethane-1,1-diyl- and benzoxazole-2-methylene-bisphosphonates vs cytotoxicity and chronic inflammation diseases. From hydrophobicity prediction to synthesis and biological evaluation.

Based on the prediction results (PASS program), a new series of α-aminophosphonate derivatives and azaphosphones was synthesized and evaluated as antitumor agents against breast-, cervical-, liver, and colon cancer diseases. The analgesic/antiinflammatory properties of the new phosphorylated pyrazoles were also investigated. The study demonstrated an efficient site selective method for making condensation products of phosphonate derivatives in high yields from carbodiimides and different types of HE reagents (74–78%) as well as dialkyl phosphites (54–65%) and hexaalkyltriamidophosphites (80–85%). Their antitumor properties against four carcinoma cell lines representing human-liver (HEPG2), -colon (HCT116), -breast (MCF7), and -cervix (HeLa) were investigated. The results showed that at least two out of the five tested phosphonates exhibited remarkable antitumor activity (IC50: 4.15–6.95 μM mL−1) when compared to the standard drugs (IC50: 5.7–9.3 μM mL−1). Nevertheless, four phosphonate products showed an analgesic capacity >80%, when compared to aspirin (73%) at the same dose of 100 mg kg−1. Furthermore, QSAR results indicated that the fused azaphosphones, thiazolopyrimidine- and pyridine-α-aminophosphonate derivatives (6 of 11 tested compounds), possess inflammatory inhibitory potency (99–117%) when compared to the standard drug (100%) after 360 min.

Carbodiimides – key mediators in the synthesis of novel cytotoxic and analgesic/antiinflammatory motifs based on α-amino-, enaminophosphonates, and azaphosphones

A variety of derivatives incorporating substituted heterocycle-phosphor motifs is described. Substituted N,P-heterocycles and derived phosphonates were produced efficiently in a tandem operation without intermediate isolation. The synthesis methodology is based on the reaction of dialkyl phosphites with Schiff base Kabachnik–Fields intermediates, which are generated in situ from 2-amino-4,6-di-tert-butylphenol and substituted benzaldehydes in dry THF/FeCl3 (10 %) solution, to yield fused oxazole-2-phosphonates in moderate yield (≈55 %). The latter products could be also obtained in excellent yield (≥76 %) by directly applying the same P(III) reagents to the parent Schiff bases. On the other hand, oxazaphosphinine-2-amines were isolated in high yields (≈77 %) when the Schiff bases were allowed to react with hexaalkyltriamidophosphites at rt. More P-heterocycles and the derived phosphonates were also obtained when the same reagents were applied to another imino derivative derived from the aminophenol, 2-hydroxybenzaldehyde oxime. The synthesized scaffolds were biologically evaluated and found to possess potent anticancer activities. On the basis of bioassay data, the produced N,P-heterocycles exhibit remarkable antitumor activity against 17 tested human tumor cell lines, representing breast and prostate cancer and melanoma. Several phosphonates were found to possess specific anti-breast cancer activity (especially MDA-MB-435 cell lines) while others possess specific effects against melanoma (MI4 and SK-MEL-2 cancer cell lines). These findings form a foundation for further investigation in our continuing efforts to develop selective anticancer agents. .

Antineoplastic activity of fused nitrogen-phosphorus heterocycles and derived phosphonates

1,3-Diphenyl-2-(hydroxyimino)-1,3-propanedione 1 reacted with phosphonium ylides 2a,b to give mainly the substituted 1-hydroxy-2,3-dihydropyrroles 6a,b along with the novel ylides 10a,b whereas the phosphono substituted-N-heterocycles lla,b and 14a,b were obtained from the reaction of I with α-phosphoryl carbanion counterparts 3a,b. Reaction of 1 with cyanomethylene(tri-phenyl)phosphorane 2c afforded the Wittig product 17 and the oxazole derivative 18 while the phosphono 2,2-disubstituted dihydrooxazole 20 and the diolefin 19 were produced in the reaction with the phosphonate ylide 3c. Application of the unsaturated carbanions 2d and 3d on 1 yielded the pyrrole 23 and the phosphono substituted 2H-1,4-oxazine 25, respectively.

Reham F. Barghash

Papers

Carbodiimides in the synthesis of enamino- and α-aminophosphonates as peptidomimetics of analgesic/antiinflammatory and anticancer agents.

Design of new arylamino-2-ethane-1,1-diyl- and benzoxazole-2-methylene-bisphosphonates vs cytotoxicity and chronic inflammation diseases. From hydrophobicity prediction to synthesis and biological evaluation.

Carbodiimides – key mediators in the synthesis of novel cytotoxic and analgesic/antiinflammatory motifs based on α-amino-, enaminophosphonates, and azaphosphones

Antineoplastic activity of fused nitrogen-phosphorus heterocycles and derived phosphonates

A Comparison of Phosphonium and Phosphonate Carbanion Reagents inReactions with 1,3-Diphenyl-2-(hydroxyimino)-1,3-propanedione