Experimental Determination of the Standard Enthalpy of Formation of Trimellitic Acid and Its Prediction by Supervised Learning.

The standard molar enthalpy of formation for trimellitic acid (TMAc) in the crystalline phase at 298.15 K, ΔfHm°(cr), was calculated experimentally from the enthalpy of combustion through combustion calorimetry experiments. Likewise, the standard molar enthalpy of sublimation was determined from the standard molar enthalpy of fusion and from the standard molar enthalpy of vaporization from differential scanning calorimetry and thermogravimetry, respectively. Subsequently, the standard molar enthalpies of formation in the gas-phase at 298.15 K, ΔfHm°(g), were calculated. The enthalpies of formation for TMAc, hemimellitic, and trimesic acids were predicted using multiple linear regression (MLR) with a nonreplacement evaluation technique. MLR was applied to the data set that allowed estimating these thermochemical properties with an R2 greater than 0.99. This model was used to compare the predicted and experimental results for benzene carboxylic acids.

n-Tuples on Scaffold Diversity Inspired by Drug Hybridisation to Enhance Drugability: Application to Cytarabine.

A mathematical concept, n-tuples are originally applied to medicinal chemistry, especially with the creation of scaffold diversity inspired by the hybridisation of different commercial drugs with cytarabine, a synthetic arabinonucleoside derived from two marine natural products, spongouridine and spongothymidine. The new methodology explores the virtual chemical-factorial combination of different commercial drugs (immunosuppressant, antibiotic, antiemetic, anti-inflammatory, and anticancer) with the anticancer drug cytarabine. Real chemical combinations were designed and synthesised for 8-duples, obtaining a small representative library of interesting organic molecules to be biologically tested as proof of concept. The synthesised library contains classical molecular properties regarding the Lipinski rules and/or beyond rules of five (bRo5) and is represented by the covalent combination of the anticancer drug cytarabine with ibuprofen, flurbiprofen, folic acid, sulfasalazine, ciprofloxacin, bortezomib, and methotrexate. The insertion of specific nomenclature could be implemented into artificial intelligence algorithms in order to enhance the efficiency of drug-hunting programs. The novel methodology has proven useful for the straightforward synthesis of most of the theoretically proposed duples and, in principle, could be extended to any other central drug.

Transition metal-free [2,3]-sigmatropic rearrangement in the reaction of sulfur ylides with allenoates.

An unprecedented transition metal free [2,3]-sigmatropic rearrangement involving stabilized sulfur ylides and allenoates has been thoroughly established. The scope and utility of this reaction have been extensively studied resulting in C-C bond formation under mild conditions with greater than 20 examples reported. A highlight of the work is the simple and fully operational process that does not involve the use of carbenes or the associated hazardous and sensitive reagents. The reaction can be performed at room temperature and using an open flask. Interestingly, the new C-C bond formation reaction is gram scalable, and the obtained isomers are readily separable, affording interesting building blocks that can be used in the preparation of complex molecules.

Green Synthesis of Silver Nanoparticles and Its Combination with Pyropia columbina (Rhodophyta) Extracts for a Cosmeceutical Application.

We report the green synthesis of silver nanoparticles (AgNPs) by using daisy petals (Bellis perennis), leek (Allium porrum) and garlic skin (Allium sativum) as reducing agents and water as solvent. AgNPs are obtained with high monodispersity, spherical shapes and size ranging from 5 to 35 nm and characterized by UV-Vis and TEM techniques. The obtained yields in AgNPs are in concordance with the total phenolic content of each plant. We also study the incorporation of AgNPs in combination with the red algae Pyropia columbina extracts (PCE) into cosmetic formulations and analyze their combined effect as photoprotective agents. Moreover, we carry out the inclusion of the PCE containing mycosporine-like amino acids (MAAs), which are strong UV-absorbing and antioxidant compounds, into ß-cyclodextrin (ßCD) and pNIPAM nanoparticles and analyze stability and release. The thermoresponsive polymer is grown by free radical polymerization using N-isopropylacrylamide (NIPAM) as the monomer, N,N'-methylenebisacrylamide (BIS) as the cross-linker, and 2,2'-azobis(2-methylpropionamidene) (V50) as the initiator, while ßCD complex is prepared by heating in water. We evaluate the nanoparticle and ßCD complex formation by UV-Vis and FT-IR, and NMR spectroscopies, respectively, and the nanoparticles' morphology, including particle size, by TEM. The cosmetic formulations are subsequently subjected to accelerated stability tests and photoprotective analyses: a synergistic effect in the combination of AgNPs and PCE in photoprotection was found. It is not related to a UV screen effect but to the antioxidant activity, having potential against photoaging.

7-Methoxy-4-methylcoumarin: Standard Molar Enthalpy of Formation Prediction in the Gas Phase Using Machine Learning and Its Comparison to the Experimental Data.

Experimentally, the standard molar enthalpy of formation in the crystalline phase at 298.15 K, ΔfHm°(cr) for 7-methoxy-4-methylcoumarin (7M4MC) was calculated by traditional linear regression, which was obtained by combustion calorimetry. Similarly, the standard molar enthalpy of sublimation was determined through the standard molar enthalpy of fusion and by the standard molar enthalpy of vaporization, from differential scanning calorimetry and thermogravimetry, respectively; lately using these results, the standard molar enthalpy of formation in the gas phase was calculated at 298.15 K, ΔfHm°(g). In addition ML was used to predict the standard molar enthalpy of formation in the gas phase for the 7M4MC, constructing an experimental data set containing three kinds of functional groups: esters, coumarins, and aromatic compounds. The procedure was performed by using multiple linear regression algorithms and stochastic gradient descent with a R2 of 0.99. The obtained models were used to compare those predicted values versus experimental for coumarins, resulting in an average error rate of 9.0%. Likewise, four homodesmic reactions were proposed and predicted with the multiple linear regression algorithm of ML obtaining good results.

The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria.

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry.

Nanoscale Biocompatible Structures Generated from Fluorinated Tripodal Phenylenes on Gold Nanoprisms.

Modification of gold substrates with a stable, uniform and ultrathin layer of biocompatible materials is of tremendous interest for the development of bio-devices. We present the fabrication of hybrid systems consisting of triangular prism gold nanoparticles (Au@NTPs) covalently covered with tripod-shaped oligo(p-phenylenes) featuring trifluoromethyl groups. Their synthesis is accomplished using a biphenyl boronic ester as the key compound. Au@NTPs were prepared through a seedless procedure using 3-butenoic acid and benzyldimethyl ammonium chloride, and modified with aminothiol groups. Coverage of this amine-modified gold substrate with a self-assembled monolayer (SAM) of tripod-shaped molecules is carried out in ethanolic solution. The hybrid system avoids up to 70 % of protein corona formation, and allows unspecific attachment for bulky adsorbates, providing an optimal biosensing platform. Chemical composition and morphology are analyzed by transmission electron microscopy (TEM), UV-visible spectroscopy and field emission scanning electron microscopy (FESEM).

Scaling Laws in the Diffusive Release of Neutral Cargo from Hollow Hydrogel Nanoparticles: Paclitaxel-Loaded Poly(4-vinylpyridine).

We study the nonequilibrium diffusive release of electroneutral molecular cargo encapsulated inside hollow hydrogel nanoparticles. We propose a theoretical model that includes osmotic, steric, and short-range polymer-cargo attractions to determine the effective cargo-hydrogel interaction, ueff*, and the effective diffusion coefficient of the cargo inside the polymer network, Deff*. Using dynamical density functional theory (DDFT), we investigate the scaling of the characteristic release time, τ1/2, with the key parameters involved in the process, namely, ueff*, Deff*, and the swelling ratio. This effort represents a full study of the problem, covering a broad range of cargo sizes and providing predictions for repulsive and attractive polymer shells. Our calculations show that the release time through repulsive polymer networks scales with q2eßueff*/Deff* for ßueff* ≫ 1. In this case, the cargo molecules are excluded from the shell of the hydrogel. For attractive shells, the polymer retains the cargo molecules on its internal surface and its interior, and the release time grows exponentially with the attraction strength. The DDFT calculations are compared to an analytical model for the mean first passage time, which provides an excellent quantitative description of the kinetics for both repulsive and attractive shells without fitting parameters. Finally, we apply the method to reproduce experimental results on the release of paclitaxel from hollow poly(4-vinylpyridine) nanoparticles and find that the slow release of the drug can be explained in terms of the strong binding attraction between the drug and the polymer.

Engaging Allene-Derived Zwitterions in an Unprecedented Mode of Asymmetric [3+2]-Annulation Reaction.

Catalytic addition of chiral phosphine, that is, (R)- or (S)-SITCP, to an α-substituted allene ester generated a zwitterionic dipole. Under optimized reaction conditions, this dipole could engage isatine-derived N-Boc-ketimines in a novel mode of [3+2] annulation reaction. Pyrrolinyl spirooxindoles are thus afforded in high yields and with excellent enantioselectivities. The unprecedented annulation reaction successfully facilitated the construction of sp(3) -rich and highly substituted 3,2'-pyrrolidinyl spirooxindoles supporting many chiral centers.

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery.

Scaffold diversity is a crucial feature of compound collections that has a huge impact on their success in biological screenings. The synthesis of highly complex and diverse scaffolds, which could be based on natural products, for example, is an arduous task that requires expertise in various aspects of organic synthesis and structural analysis. This challenge has been addressed by a number of synthesis designs, which employ natural products as a source of scaffold diversity, transform suitably designed common intermediates into various molecular frameworks, or entail highly concise synthetic routes to a number of distinct and complex scaffolds. In this Minireview, we highlight recent synthetic developments towards the construction of diverse and complex scaffolds and the application of the resulting compound collections in drug and probe discovery.

De novo branching cascades for structural and functional diversity in small molecules.

The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and thus calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Here we present a de novo branching cascades approach wherein simple primary substrates follow different cascade reactions to create various distinct molecular frameworks in a scaffold diversity phase. Later, the scaffold elaboration phase introduces further complexity to the scaffolds by creating a number of chiral centres and incorporating new hetero- or carbocyclic rings. Thus, employing N-phenyl hydroxylamine, dimethyl acetylenedicarboxylate and allene ester as primary substrates, a compound collection of sixty one molecules representing seventeen different scaffolds is built up that delivers a potent tubulin inhibitor, as well as inhibitors of the Hedgehog signalling pathway. This work highlights the immense potential of cascade reactions to deliver compound libraries enriched in structural and functional diversity.

Experimental and Computational Thermochemistry of 3- and 4-Nitrophthalic Anhydride.

In order to understand the influence that the position of the nitro group on the aromatic ring has on the relative stability of two isomers, the standard enthalpies of formation of 3- and 4-nitrophthalic anhydride in the gaseous phase, at T = 298.15 K, were obtained by experimental thermochemistry and theoretical studies. The standard enthalpies of formation in the crystalline phase, at T = 298.15 K, were obtained by combustion calorimetry and the enthalpies of sublimation by the Knudsen method. For the theoretical calculations, a standard ab initio molecular orbital method at the G3 level was used. The enthalpies of formation in the gaseous phase were obtained from atomization and isodesmic reactions. A theoretical study of the molecular and electronic structures of these compounds was also performed. Differences of -9.7 kJ·mol-1, for 3-nitrophthalic anhydride, and -2.6 kJ·mol-1 for 4-nitrophthalic anhydride, were found from a comparison between our theoretical and experimental results.

A highly stereoselective synthesis of glycidic amides based on a new class of chiral sulfonium salts: applications in asymmetric synthesis.

A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from α-amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans-epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98%). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane-ring-opening reactions with different types of nucleophiles.

Cyclic sulfur ylides derived from Gleason-type chiral auxiliaries for the asymmetric synthesis of epoxy amides.

Gleason-type chiral auxiliaries were used for the synthesis of a novel class of sulfonium salts, obtained via methylation of the sulfide with Meerwein's salt. The salts were reacted with aldehydes under basic conditions to provide epoxy amides, which were reduced to their corresponding epoxy alcohols in excellent enantiomeric excesses. Interestingly, it was feasible to synthesize both enantiomeric epoxy alcohols depending on which of the sulfonium salts, prepared from L-amino acids (6 and 9 from L-valine or 15 and 16 from L-serine) was employed.

A highly efficient methodology of asymmetric epoxidation based on a novel chiral sulfur ylide.

A new type of chiral sulfur ylides has been synthesized and their reactivities against carbonyl compounds tested, showing a high degree of stereoselectivity in the formation of trans epoxy amides under very mild reaction conditions.

Epoxyamide-based strategy for the synthesis of polypropionate-type frameworks.

A new approach to the stereoselective synthesis of polypropionate-type frameworks is reported utilizing reactions of amide-stabilized sulfur ylides with chiral aldehydes. To establish a new strategy for macrolide fragment synthesis, the stereoselectivity of these reactions in the construction of epoxy amides was the most important aspect of this study. In this aspect, we found a strong influence of the protecting groups employed in the starting aldehydes upon the stereochemical outcome of their reactions with the sulfur ylide 1. Thus, numerous aldehydes showed remarkable stereofacial differentiation, providing a major diastereoisomer, in contrast to others that displayed a poor or no stereoselectivity. Despite the difficulties encountered for some cases with respect to their diastereomeric yields, we were able to prepare various stereotetrads and stereopentads, thus enhancing the synthetic value of this new methodology for the preparation of typical polypropionate frameworks found in many natural products, in particular the macrolide class of antibiotics.

Stereoselective synthesis of macrolide-type antibiotics from epoxy amides. Synthesis of the polypropionate chain of streptovaricin u.

The synthesis of the polypropionate chain of Streptovaricin U (1) is described utilizing a new approach for the stereoselective synthesis of the macrolide-type antibiotics via sulfur ylides.

Synthetic studies on stevastelins. 2. Synthesis of lipidic- and peptidic-modified analogues.

[Chemical reaction: See text] The synthesis of a series of stevastelin analogues with modification of the susbstituent at the C-2 position of the stearic acid chain (compounds 28 and 31), variation of the amino acids (compounds 41, 42, 73, and 78), or lacking the lipidic chain (compound 91) is described. The replacement of L-valine and L-threonine with other amino acids proceeded without difficulties for the synthesis of analogues 41 and 42; however, the substitution of L-serine with simple amino acids, such as glycine or L-alanine, proved to be elusive, which was adscribed to factors of conformational flexibility. Finally, the substitution with L-valine or L-threonine proceeded without difficulties to provide the analogues 73 and 78 respectively.