Anticancer Activity of Nonpolar Pt(CH3)2I2{bipy} is Found to be Superior among Four Similar Organoplatinum(IV) Complexes.

The anticancer properties of well-defined molecules serve to bolster the field of metals in medicine. Such compounds, particularly those of platinum and their closely related structural analogs, continue to be potentially highly interesting to researchers and clinicians alike. The four octahedral organoplatinum(IV) compounds [Pt(CH3)2X2{bipy-R 2 }] (X = Br, I; bipy-R 2 = 2,2'-bipyridine, 2,2'-bipyridine-4,4'-dicarboxylic acid) have been isolated and structurally characterized by single-crystal X-ray diffraction. Nuclear magnetic resonance and infrared spectroscopic data are also tabulated as useful reference values. The anticancer potential of each compound was assessed via in vitro MTT assays, using human breast cancer cells (cell line ZR-75-1). EC50 values were determined as 11.5 µM for Pt(CH3)2Br2{bipy}; 3020 µM, for Pt(CH3)2Br2{bipy-(CO 2 H) 2 }; 6.1 µM, for Pt(CH3)2I2{bipy}; and 86.0 µM, for Pt(CH3)2I2{bipy-(CO 2 H) 2 }; for comparison, the EC50 value for cisplatin against the ZR-75-1 cells was 16.4 µM. The most cytotoxic of the four compounds Pt(CH3)2I2{bipy} undergoes reaction with glutathione in a THF/water mixture at 68°C very slowly.

Asymmetric Synthesis of Bicyclic Pyrazolidinones through Alkaloid-Catalyzed [3+2]-Cycloadditions of Ketenes and Azomethine Imines.

A versatile asymmetric synthesis of bicyclic pyrazolidinones through alkaloid-catalyzed formal [3+2]- and [3+2+2]-cycloadditions of ketenes with azomethine imines is described. The methodology was found to be tolerant of ketene and a variety of monosubstituted ketenes (R=alkyl, OAc). The products were formed in good to excellent yields (71-99 % for 24 examples, 39 examples in all), with good to excellent diastereoselectivity in many cases (dr 3 : 1 to 27 : 1 for 22 examples), and with excellent enantioselectivity for most examples (≥93 % ee for 34 products). In the case of most disubstituted ketenes, the reaction proceeded through a [3+2+2]-cycloaddition to form structurally interesting bicyclic pyrazolo-oxadiazepinediones with moderate diastereoselectivity (dr up to 3.7 : 1) and as racemic mixtures (3 examples). The method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3-dipole.

Recent Advances in the Synthesis of Isoquinoline-Fused Benzimidazoles.

This review includes recent developments in the synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines with particular attention given to categorizing protocols based on the structural features of the ring architecture and crystallographically characterized reaction products.

Asymmetric Synthesis of γ-Lactones through Koga Amine-Controlled Addition of Enediolates to α,ß-Unsaturated Sulfoxonium Salts.

A chiral Koga amine-controlled asymmetric synthesis of cis-γ-lactones through a formal [3 + 2] cycloaddition of enediolates with α,ß-unsaturated sulfoxonium salts is described. The desired structural motif was formed in moderate to good yields (50-71% for 13 examples), with good to very good diastereoselectivity (dr 5:1 to 10:1 for 20 examples), favoring the cis-isomer, and good to excellent enantioselectivity (70-91% ee for 13 examples).

Multicomponent reaction through cooperative trio catalysis incorporating enamine, Brønsted acid and metal Lewis acid catalysis: a concise route to access chromans.

An atom-economical multicomponent cascade reaction of salicylaldehydes, cyclohexanones and arylamines has been developed for the synthesis of three-ring fused chromans. This reaction was achieved through cooperative enamine-metal Lewis acid assisted Brønsted acid catalysis, furnishing the products in excellent yields with good diastereoselectivity.

Monitoring a simple hydrolysis process in an organic solid by observing methyl group rotation.

We report a variety of experiments and calculations and their interpretations regarding methyl group (CH3) rotation in samples of pure 3-methylglutaric anhydride (1), pure 3-methylglutaric acid (2), and samples where the anhydride is slowly absorbing water from the air and converting to the acid [C6H8O3(1) + H2O → C6H10O4(2)]. The techniques are solid state 1H nuclear magnetic resonance (NMR) spin-lattice relaxation, single-crystal X-ray diffraction, electronic structure calculations in both isolated molecules and in clusters of molecules that mimic the crystal structure, field emission scanning electron microscopy, differential scanning calorimetry, and high resolution 1H NMR spectroscopy. The solid state 1H spin-lattice relaxation experiments allow us to observe the temperature dependence of the parameters that characterize methyl group rotation in both compounds and in mixtures of the two compounds. In the mixtures, both types of methyl groups (that is, molecules of 1 and 2) can be observed independently and simultaneously at low temperatures because the solid state 1H spin-lattice relaxation is appropriately described by a double exponential. We have followed the conversion 1 → 2 over periods of two years. The solid state 1H spin-lattice relaxation experiments in pure samples of 1 and 2 indicate that there is a distribution of NMR activation energies for methyl group rotation in 1 but not in 2 and we are able to explain this in terms of the particle sizes seen in the field emission scanning electron microscopy images.

Phosphine-Catalyzed Diastereoselective Synthesis of ß-Lactones from Disubstituted Ketenes and α-Chiral Oxyaldehydes.

In this article we describe a catalytic procedure for the diastereoselective synthesis of ß-lactones bearing two stereogenic centers, from disubstituted ketenes and α-chiral oxyaldehydes. Tri-n-butylphosphine was found to be the optimal catalyst in terms of effecting both good yield and diastereoselectivity (dr from 3:1 to 32:1 for 8 examples) in ß-lactone formation. The major isomer of the ß-lactone products was determined to be the anti-diastereomer, and its formation was rationalized by a polar Felkin-Anh model. Involvement of phosphonium enolate intermediates in the reaction mechanism was indicated through reaction monitoring by (31)P NMR spectroscopy. The utility of the methodology is demonstrated by a short synthesis of a (+)-peloruside A synthon.

Phosphine-catalyzed asymmetric synthesis of ß-lactones from disubstituted ketenes and aldehydes.

In this article we describe a general catalytic procedure for the formation of ß-lactones bearing two stereogenic centers, from disubstituted ketenes and achiral aldehydes. BINAPHANE was found to display excellent enantioselectivity (≥90% ee for eight examples) and good diastereoselectivity (≥90:10 for 13 examples) in catalyzing the formation of ß-lactones bearing two stereogenic centers from achiral aldehydes (both aromatic and aliphatic) and alkylarylketenes or dialkylketenes. A preference for formation of the trans diastereomer was observed in these reactions. For those reactions where BINAPHANE failed as a catalyst, tri-n-butylphosphine was found to be an effective achiral nucleophilic catalyst, effecting good yield and diastereoselectivity in racemic ß-lactone formation. Evidence for the involvement of phosphonium enolate intermediates in the reaction mechanism was obtained through reaction monitoring by (31)P NMR spectroscopy and by comparison with previously characterized intermediates observed in the phosphine-catalyzed ketene homodimerization reaction.

Dual space divergence in small molecule quasiracemates: benzoyl leucine and phenylalanine assemblies.

Quasiracemic materials constructed with two points of structural difference were used to understand the role molecular shape plays in molecular assembly. Hot stage, crystallographic and occupied cavity space assessments provide insight into how imposed CH3/Cl and H/CF3 structural variations placed on benzoyl leucine and phenylalanine scaffolds result in a remarkably high occurrence of cocrystal formation.

Synthesis, Structure and Anticancer Activity of a Dinuclear Organoplatinum(IV) Complex Stabilized by Adenine.

The dinuclear organoplatinum(IV) compound {Pt(CH3)3}2(µ-I)2(µ-adenine) (abbreviated Pt2ad), obtained by treating cubic [Pt(CH3)3(µ3-I)]4 with two equivalents of adenine, was isolated and structurally characterized by single crystal X-ray diffraction. The National Cancer Institute Developmental Therapeutics Program's in vitro sulforhodamine B assays showed Pt2ad to be particularly cytotoxic against central nervous system cancer cell line SF-539, and human renal carcinoma cell line RXF-393. Furthermore, Pt2ad displayed some degree of cytotoxicity against non-small cell lung cancer (NCI-H522), colon cancer (HCC-2998, HCT-116, HT29, and SW-620), melanoma (LOX-IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-28, and UACC-62), ovarian cancer (OVCAR-5), renal carcinoma (A498), breast cancer (BT-549 and MDA-MB-468), and triple-negative breast cancer (MDA-MB-231).

Benzoyl Valine Quasiracemates: Pairing CF3 Quasienantiomers with H to t-Butyl.

Understanding the interplay of structural features responsible for molecular assembly is essential for molecular crystal engineering. When assembling molecules with encoded motifs, first choice supramolecular strategies almost always include robust directional nonbonded contacts. Quasiracemic materials, considered near racemates since cocrystallization occurs with chemically unique components, lack a molecular framework or functional group restrictions, highlighting the importance of molecular shape to molecular assembly. Recently, our group reported quasiracemates derived from benzoyl leucine/phenylalanine derivatives with two points of chemical difference. In this study, we modified the chemical framework with valine and increased the scope of the work by imposing a larger variance in the side chain substituents. Pairing a CF3 component with quasienantiomers that differ iteratively from hydrogen to t-butyl offers an important view into the supramolecular landscape of these materials. Single-crystal X-ray crystallography and lattice energy assessments, coupled with conformational and crystal structure similarity searches, show an elevated degree of isomorphism for many of the targeted 17 racemates and quasiracemates. These benzoyl amino acid molecular architectures create extended hydrogen-bond patterns in the crystal that provide enhanced opportunities to study the shape space and molecular recognition profiles for a diverse family of quasienantiomeric components.

Diastereoselective reaction of sulfoxonium ylides, aldehydes and ketenes: an approach to trans-γ-lactones.

In this paper, a novel approach to γ-lactones from the reaction of sulfoxonium ylides, aldehydes, and ketenes is described. The new ylide-based method provides access to γ-lactones from disubstituted ketenes, in good yields, and with good diastereoselectivity favoring the trans-diastereomer (11 examples with dr ≥ 82:18, dr up to 92:8).

Crystal structure and Hirshfeld surface analysis of tri-aza-triborinotris[1,3,2]benzodi-aza-borole acetone disolvate.

The title compound, alternatively known as benzodi-aza-borole trimer, C18H15B3N6·2C3H6O, at 100 K crystallizes in the triclinic system, space group P . The structure displays N-H⋯O hydrogen bonding connecting the main mol-ecule with the crystallization solvent. Disorder of the main mol-ecule is observed with occupancy factors refined to 0.8922 (14):0.1078 (14). The packing of the crystal shows a parallel-displaced atom-centered orientation with 3.30 (2) Šbetween the planes of the rings. In the solid state, the title compound is linked with weak C-H⋯π inter-actions, which is supported by Hirshfeld surface analysis.

Neutrophil-Mediated Delivery of Nanocrystal Drugs via Photoinduced Inflammation Enhances Cancer Therapy.

The efficient delivery of anticancer agents into tumor microenvironments is critical for the success of cancer therapies, but it is a prerequisite that drug carriers should overcome tumor vasculature and possess high drug contents. Here, we found that photoinduced inflammation response caused the migration of neutrophils into tumor microenvironments and neutrophils transported neutrophil-targeted nanoparticles (NPs) across the tumor blood barrier. The results showed that tumor delivery efficiencies of NPs were 5% ID/g, and they were independent of particle sizes (30-200 nm) and their doses (108-1011 NPs). To efficiently deliver anticancer agents into tumors via neutrophils, we fabricated carrier-free paclitaxel nanocrystals (PTX NC). The results showed that neutrophil uptake of PTX NC did not impair neutrophil tumor infiltration, and the sustainable release of PTX from PTX NC in tumors was regulated by paclitaxel protein complexes, thus improving the mouse survival in two preclinical models. Our studies demonstrate that delivery of nanocrystal drugs via neutrophils is a promising method to effectively treat a wide range of cancers, and we have also identified a mechanism of drug release from neutrophils in tumors.

Synthesis and Determination of Anticancer Activity of Dicobalt Hexacarbonyl 2'-Deoxy-5-alkynylfuropyrimidines.

Dicobalt hexacarbonyl 5-alkynyl furopyrimidine nucleoside analogs, with 4-methylphenyl (p-tolyl) and 4-pentylphenyl substituents attached at the C-6 base position, designed in the form of ribose acetyl esters, were synthesized (42-96%). Attached at the C-5 position were propargyl alcohol, its methyl ether and acetate derivatives, butynol, and the 4-methylphenyl- (p-tolyl) and 4-pentylphenyl-substituted alkynyl groups, which were coordinated to a dicobalt hexacarbonyl unit. The structure of 5-(3-acetoxyprop-1-yn-1-yl)-6-p-tolyl-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one was determined by X-ray crystallography. Density functional theory calculations performed on the corresponding derivative yielded geometric parameters for the dicobalt hexacarbonyl adduct of this ligand. The cytotoxic activity of each of dicobalt modified nucleosides on cancer cells of different phenotypes was determined in vitro. The investigated compounds showed antiproliferative effects with median inhibitory concentration (IC50) values in the ranges of 14-90 and 9-50 µM for HeLa and K562 cells, respectively. The formation of reactive oxygen species in the presence of modified nucleosides was determined in K562 cells. The results indicate that the mechanism of action for the studied compounds may be related to the induction of oxidative stress.

Crystal structures, Hirshfeld analysis, and energy framework analysis of two differently 3'-substituted 4-methylchalcones: 3'-(N=CHC6H4-p-CH3)-4-methylchalcone and 3'-(NHCOCH3)-4-methylchalcone.

Two crystal structures of chalcones, or 1,3-diarylprop-2-en-1-ones, are presented; both contain a p-methyl substitution on the 3-Ring, but differ with respect to the m-substitution on the 1-Ring. Their systematic names are (2E)-3-(4-methylphenyl)-1-(3-{[(4-methylphenyl)methylidene]amino}phenyl)prop-2-en-1-one (C24H21NO) and N-{3-[(2E)-3-(4-methylphenyl)prop-2-enoyl]phenyl}acetamide (C18H17NO2), which are abbreviated as 3'-(N=CHC6H4-p-CH3)-4-methylchalcone and 3'-(NHCOCH3)-4-methylchalcone, respectively. Both chalcones represent the first reported acetamide-substituted and imino-substituted chalcone crystal structures, adding to the robust library of chalcone structures within the Cambridge Structural Database. The crystal structure of 3'-(N=CHC6H4-p-CH3)-4-methylchalcone exhibits close contacts between the enone O atom and the substituent arene ring, in addition to C...C interactions between the substituent arene rings. The structure of 3'-(NHCOCH3)-4-methylchalcone exhibits a unique interaction between the enone O atom and the 1-Ring substituent, contributing to its antiparallel crystal packing. In addition, both structures exhibit π-stacking, which occurs between the 1-Ring and R-Ring for 3'-(N=CHC6H4-p-CH3)-4-methylchalcone, and between the 1-Ring and 3-Ring for 3'-(NHCOCH3)-4-methylchalcone.

Synthesis and structural investigation of an "oxazinoquinolinespirohexadienone" that only exists as its long-wavelength ring-opened quinonimine isomer.

The spirocyclic oxazinoquinolinespirohexadienone (OSHD) "photochromes" are computationally predicted to be an attractive target as electron deficient analogues of the perimidinespirohexadienone (PSHD) photochromes, for eventual application as photochromic photooxidants. We have found the literature method for their preparation unsuitable and present an alternative synthesis. Unfortunately the product of this synthesis is the long wavelength (LW) ring-opened quinonimine isomer of the OSHD. We have found this isomer does not close to the spirocyclic short wavelength isomer (SW) upon prolonged standing in the dark, unlike other PSHD photochromes. The structure of this long wavelength isomer was found by NMR and X-ray crystallography to be exclusively the quinolinone (keto) tautomer, though experimental cyclic voltammetry supported by our computational methodology indicates that the quinolinol (enol) tautomer (not detected by other means) may be accessible through a fast equilibrium lying far toward the keto tautomer. Computations also support the relative stability order of keto LW over enol LW over SW.

Room temperature syntheses of entirely diverse substituted ß-fluorofurans.

Synthesis of highly substituted 3-fluorofurans is reported. The sequence began with preparation of tert-butyldimethylsilyl alk-1-en-3-yn-1-yl ethers from 1,4-disubstituted alk-3-yn-1-ones. Subsequent fluorination of alkenynyl silyl ethers with Selectfluor gave 2-fluoroalk-3-yn-1-ones in almost quantitative yield. Subsequent 5-endo-dig cyclizations using chlorotriphenylphosphine gold(I)/silver trifluoromethanesulfonate (5/5 mol%), N-bromo- or N-iodosuccinimide and gold(I) chloride/zinc bromide (5/20 mol%), all at room temperature, provided a facile method for the generation of substituted 3-fluoro-, 3-bromo-4-fluoro-, and 3-fluoro-4-iodofurans in good yields. Also, 2,2-difluoroalk-3-yn-1-ones were prepared by fluorination of alk-3-yn-1-ones under organocatalytic conditions. The structures of (Z)-tert-butyldimethylsilyl but-1-en-3-yn-1-yl ether, 3-bromo-4-fluorofuran, and 3-fluoro-4-(phenylethynyl)furan were confirmed by X-ray crystallography.

Synthesis of diversely 1,3,5-trisubstituted pyrazoles via 5-exo-dig cyclization.

5-Exo-dig cyclocondensation of alk-3-yn-1-ones with hydrazines, in the presence of montmorillonite K-10, provides an effective method with a high atom economy for the synthesis of diversely 1,3,5-trisubstituted pyrazoles. The microwave-accelerated reaction proceeds in the absence of solvent and leads to 5-benzyl substituted pyrazoles with good yields (72-91%). The regiochemistry of the process was confirmed by the X-ray crystallographic structure determination of 1-(2-fluorophenyl)-5-(4-methylbenzyl)-3-phenyl-1H-pyrazole.

Parallel synthesis of peptide-like macrocycles containing imidazole-4,5-dicarboxylic acid.

We prepared a series of peptide-like 14-membered macrocycles containing an imidazole-4,5-dicarboxylic acid scaffold by using known coupling reagents and protecting group strategies. Yields of the purified macrocycles were poor on average, yet seemingly independent of amino acid substitution or stereochemistry. The macrocycles retain some level of conformational variability as observed by both molecular modeling and X-ray crystallography. These macrocycles represent a new class of structures for further development and for future application in high-throughput screening against a variety of biological targets.