Complex Molecules Research Articles

Understanding the behavior of a potential anticancer lamotrigine in explicit solvent (water and DMSO) using quantum mechanical tools and abinitio molecular dynamics

Lamotrigine is a medication used to treat epilepsy and help stabilize mood in individuals with bipolar disorder. Epilepsy includes different types of seizures, such as focal seizures, tonic-clonic seizures, and Lennox-Gastaut syndrome, and Lamotrigine is specifically designed to manage this condition. The effectiveness of the drug relies on how it interacts with different liquid environments. In our study, we employed two methods, namely PBE0-D3/def2-TZVP, for optimizations and various calculations. We utilized this approach for NBO, NCI, and wavefunction assay. Additionally, we used PBE0-D3/def2-TZVP and DLPNO-CCSD(T) for analyzing LED, MD, and the bond energy of Lamotrigine in both a vacuum and a complex setting (with water and DMSO). Our findings revealed that Lamotrigine can break down into four fragments: triazine, dichlorophenyl-, 10 amine at the second position in triazine, and 10 amines at the fourth position in triazine. The bond energy for these fragments is measured at 351.84 kcal/mol. NBO provided insights into the electronic transition energies of Lamotrigine in different environments, including a vacuum and with solvents. NCI helped us understand the non-covalent interactions of Lamotrigine in both a vacuum and with water and DMSO (complex) molecules through their two pores: inter and intra interactions. We further explored binding energies and total binding energies of Lamotrigine with water and DMSO. Simulations indicated that Lamotrigine with DMSO pore1 exhibited the highest energy changes over time with a positive sign, while Lamotrigine with water pore2 showed the lowest energy changes over time with a negative sign. In our implicit solvation assay using the SMD model and the CPCM method, we found that Lamotrigine with water had a lower free energy compared to the Lamotrigine-DMSO system.

Retrosynthesis Zero: Self-Improving Global Synthesis Planning Using Reinforcement Learning.

The field of computer-aided synthesis planning (CASP) has witnessed significant growth in recent years. Still, many CASP programs rely on large data sets to train neural networks, resulting in limitations due to the data quality and prior knowledge from chemists. In response, we propose Retrosynthesis Zero (ReSynZ), a reaction template-based method that combines Monte Carlo Tree Search with reinforcement learning inspired by AlphaGo Zero. Unlike other single-step reaction template-based CASP methods, ReSynZ takes complete synthesis paths for complex molecules, determined by reaction rules, as input for training the neural network. ReSynZ enables neural networks trained with relatively small reaction data sets (tens of thousands of data) to generate multiple synthesis pathways for a target molecule and suggest possible reaction conditions. On multiple data sets of molecular retrosynthesis, ReSynZ demonstrates excellent predictive performance compared to existing algorithms. The advantages, such as self-improving model features, flexible reward settings, the potential to surpass human limitations in chemical synthesis route planning, and others, make ReSynZ a valuable tool in chemical synthesis design.

Copper-Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage Functionalization.

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

Photochemical Synthesis and Ring‐Opening of Aziridines and Epoxides: State‐of‐the‐Art

The development of greener methods for the preparation of three‐membered rings has increased in the last decade, not only due to their biological activity, but also by the ring strain of those heterocycles that make them useful precursors of more complex molecules. In this work, the visible‐light‐promoted synthesis and ring‐opening of aziridines and epoxides, reported in the last five years, were reviewed. Both homogeneous and heterogeneous catalysts were discussed and, in addition, the plausible mechanism pathways were highlighted.

Perfluorooxosulfate Salts as SOF4‐Gas‐Free Precursors to Multidimensional SuFEx Electrophiles

AbstractSulfur(VI) Fluoride Exchange (SuFEx) chemistry stands as a well‐established method for swiftly constructing complex molecules in a modular fashion. An especially promising segment of this toolbox is reserved for multidimensional SuFEx hubs: three or more substituents pluggable into a singular SVI centre to make ‘beyond‐linear’ clicked constructions. Sulfurimidoyl difluorides (RNSOF2) stand out as the prime example of this, however their preparation from the scarcely available thionyl tetrafluoride (SOF4) limits this chemistry to only a few laboratories with access to this gas. In this work, we identify silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2‐mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces the sulfurimidoyl fluorides in high yields. In addition, we have found this workflow to be fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials.

Perfluorooxosulfate Salts as SOF4-Gas-Free Precursors to Multidimensional SuFEx Electrophiles.

Sulfur(VI) Fluoride Exchange (SuFEx) chemistry stands as a well-established method for swiftly constructing complex molecules in a modular fashion. An especially promising segment of this toolbox is reserved for multidimensional SuFEx hubs: three or more substituents pluggable into a singular SVI centre to make 'beyond-linear' clicked constructions. Sulfurimidoyl difluorides (RNSOF2) stand out as the prime example of this, however their preparation from the scarcely available thionyl tetrafluoride (SOF4) limits this chemistry to only a few laboratories with access to this gas. In this work, we identify silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2-mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces the sulfurimidoyl fluorides in high yields. In addition, we have found this workflow to be fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials.

Visible‐Light‐Induced Three‐Component Alkylpyridylation of Alkenes Enabled by Electron Donor‐Acceptor Complex

Visible‐light‐induced difunctionalization of alkenes is a powerful strategy for constructing complex molecules. Herein, we disclose a three‐component 1,2‐alkylpyridylation of alkenes under mild and photosensitizers‐free conditions. UV‐vis absorption spectroscopy studies and NMR titration experiments indicate that the formation of an EDA complex between 4‐alkyl‐DHPs and 4‐cyanopyridines. Primary, secondary, and tertiary C(sp3)‐centered radicals were formed by homolytic cleavage of 4‐alkyl‐DHPs. Gram‐scale synthesis and late‐stage functionalization of medicinally relevant molecules showed the synthetic potential of our methodology.

Photocatalytic Generation of Carbocation from Thiols and Application to Cross-Nucleophile Coupling.

Represented herein is a simple thiol identified as an effective precursor to photochemically form a carbocation. Thanks to the thiyl radical rapid transformation to disulfide, which serves not only to stabilize the generated thiyl radical but also to allow the second electron transfer to form a carbocation. The resulting carbocations, including primary benzylic, secondary, and tertiary carbocations, can smoothly couple with nitrogen, oxygen, and carbon nucleophilic coupling partners as well as complex drug molecules, accompanied by elemental sulfur formation in air.

Bioactivity, crystal and molecular structure of vanadyl(III) complex with N-salicyloyl − N’(3,5-ditertbutyl-2-hydroxy)benzylidene hydrazine

N-salicyloyl-N’-(3,5-ditertbutyl-2-hydroxy)benzylidene hydrazine (H3sahz) and its complex with VO(III) have been synthesized. The molecular and crystal structure of the [(VO)2(sahz)2(C2H5O)2(C2H5OH)] complex by X-ray diffraction, as well as IR and electronic spectra, EPR spectrum etc., have been studied. The structure of the investigated VO(III) complex consists of binuclear units in which the monomeric complex molecules are linked to each other through vanadyl oxygen atom. Monomeric complexes differ between themselves in the character of coordination. Both vanadium atoms have a distorted octahedral environment. The biological activity of this compound has been studied. Lastly, the activities of the studied ligand against various enzyme proteins including acetylcholinesterase (AChE), butrylcholinesterase (BChE) and α-glycosidase (α-Gly) enzyme were compared. ChE inhibitory activities of the new complex against α-Gly, AChE and BChE were determined by Tao and Ellman’s methods. The new complex was shown to have IC50 values of 42.60 µM for BChE, 91.43 µM for AChE, and 196.49 µM for α-glycosidase.

ß‐Phenethylamine Synthesis via Latent Dual Electrophilicity of N‐Pyridinium Aziridines

ß‐Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N‐pyridinium aziridines as latent dual electrophiles for the synthesis of ß‐phenethylamines. Bromide‐promoted ring opening generates ß‐halopyridinium amines. Selective Ni‐catalyzed C–C cross‐coupling between organozinc nucleophiles and the benzylic C–Br electrophile affords a diverse family of ß‐functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni‐catalyzed reductive N–N bond activation within the b‐functionalized phenethylamino‐pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N–N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N‐centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß‐phenethylamines and significantly expand the utility of N‐pyridinium aziridines as linchpins in chemical synthesis

ß-Phenethylamine Synthesis via Latent Dual Electrophilicity of N-Pyridinium Aziridines.

ß-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual electrophiles for the synthesis of ß-phenethylamines. Bromide-promoted ring opening generates ß-halopyridinium amines. Selective Ni-catalyzed C-C cross-coupling between organozinc nucleophiles and the benzylic C-Br electrophile affords a diverse family of ß-functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni-catalyzed reductive N-N bond activation within the b-functionalized phenethylamino-pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N-N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N-centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß-phenethylamines and significantly expand the utility of N-pyridinium aziridines as linchpins in chemical synthesis.

A deconstruction-reconstruction strategy for pyrimidine diversification.

Structure-Activity Relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates.1-3 Here, we present an alternative approach where we convert pyrimidine-containing compounds various other nitrogen heteroaromatics. Transforming pyrmidines into their correspondingN-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction-reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles.4 In effect, this approach allows heterocycle formation on complex molecules, resulting in analogs that would be challenging to obtain by other methods. We anticipate this deconstruction-reconstruction strategy will extend to other heterocycle classes.

Dinuclear gold-catalyzed divergent dechlorinative radical borylation of gem-dichloroalkanes

The enormous and widespread use of organoboronic acids has prompted the development of innovative synthetic methodologies to meet the demands on structural diversity and functional group tolerance. The existing photoinduced defunctionalization radical borylation, typically focused on the conversion of one C-X bond (X= Br, I, or other leaving group) into only one C-B bond. Herein, we disclose a divergent radical dechloroborylation reaction enabled by dinuclear gold catalysis with visible light irradiation. A wide range of structurally diverse alkyl boronic, α-chloroboronic, and gem-diboronic esters can be synthesized in moderate to good yields (up to 92%). Its synthetic robustness is further demonstrated on a preparative scale and applied to late-stage diversification of complex molecules. The process hinges on a C-Cl bond relay activation in readily available gem-dichloroalkanes through inner-sphere electron transfer, overcoming the redox potential limits of unreactive alkyl chlorides.

Synthesis and Biological Activity of Pyrrolizidine Alkaloids: A Review

Abstract: Pyrrolizidine alkaloids (PAs) belong to a structurally varied class of natural products that have garnered significant attention due to their intriguing chemical properties and broad range of biological activities. This review aims to provide a comprehensive overview of the synthesis and biological activity of pyrrolizidine alkaloids. An in-depth exploration of the various synthetic methodologies employed in the construction of these complex molecules, including classical and modern synthetic approaches, is presented in this review. Moreover, the potential therapeutic applications of these alkaloids are discussed, emphasizing their promising role in drug discovery and development. By synthesizing the current knowledge, this paper aims to facilitate further research in the field and inspire the discovery of novel bioactive compounds with therapeutic potential.

SuFEx-Enabled Direct Deoxy-Diversification of Alcohols.

We introduce a new use of sulfonyl fluoride as a bifunctional reagent that facilitates the one-step deoxy-diversification of complex alcohol libraries. Our reaction design features a Sulfur(VI) Fluoride Exchange (SuFEx) mediated activation of alcohols and fluoride-induced activation of silicon-bound nucleophiles. This method enables the direct conversion of alcoholic C-O bonds in complex molecules into diverse analogues via C-C, C-N, C-Cl, and C-Br bond formation while suppressing any elimination side-products.

First Detection in Space of the High-energy Isomer of Cyanomethanimine: H2CNCN

We report the first detection in the interstellar medium of N-cyanomethanimine (H2CNCN), the stable dimer of HCN of highest energy and the most complex organic molecule identified in space containing the prebiotically relevant NCN backbone. We have identified a plethora of a-type rotational transitions with 3 ≤ J up ≤ 11 and K a ≤ 2 that belong to this species toward the Galactic center G+0.693-0.027 molecular cloud, the only interstellar source showing the three cyanomethanimine isomers (including the Z- and E-isomers of C-cyanomethanimine, HNCHCN). We have derived a total column density for H2CNCN of (2.9 ± 0.1) × 1012 cm−2, which translates into a total molecular abundance with respect to H2 of (2.1 ± 0.3) × 10−11. We have also revisited the previous detection of E- and Z-HNCHCN and found a total C/N-cyanomethanimine abundance ratio of 31.8 ± 1.8 and a Z/E-HNCHCN ratio of 4.5 ± 0.2. While the latter can be explained on the basis of thermodynamic equilibrium, chemical kinetics are more likely responsible for the observed C/N-cyanomethanimine abundance ratio, where the gas-phase reaction between methanimine (CH2NH) and the cyanogen radical (CN) arises as the primary formation route.

Palladium catalyzed C(sp3)–H trifluoroethoxylation

Palladium(II) complexes of the TPA family (TPA − tris(2-pyridylmethyl)amine) have recently emerged as efficient catalysts of highly 3°-regioselective hydroxylation and chemoselective 2°-ketonization of aliphatic C–H groups with peroxycarboxylic acids. Herewith, we present a novel facet of the catalytic reactivity of such complexes that have been shown to mediate highly efficient (at as low as 0.6mol. % catalyst loadings) and selective trifluoroethoxylation of organic substrates at benzylic C–H groups, affording the corresponding trifluoroethoxy ethers in up to 73 % isolated yield. The developed synthetic protocol allows for diastereoselective trifluoroethoxylation of complex molecules of natural origin (steroids, terpenoids).

Carbene-Assisted Arene Ring-Opening.

Despite the significant achievements in dearomatization and C-H functionalization of arenes, the arene ring-opening remains a largely unmet challenge and is underdeveloped due to the high bond dissociation energy and strong resonance stabilization energy inherent in aromatic compounds. Herein, we demonstrate a novel carbene assisted strategy for arene ring-opening. The understanding of the mechanism by our DFT calculations will stimulate wide application of bulk arene chemicals for the synthesis of value-added polyconjugated chain molecules. Various aryl azide derivatives now can be directly converted into valuable polyconjugated enynes, avoiding traditional synthesis including multistep unsaturated precursors, poor selectivity control, and subsequent transition-metal catalyzed cross-coupling reactions. The simple conditions required were demonstrated in the late-stage modification of complex molecules and fused ring compounds. This chemistry expands the horizons of carbene chemistry and provides a novel pathway for arene ring-opening.

Metallophthalocyanine as ideal antibiotics without light: Mechanisms and applications

The urgent global health problem of antimicrobial resistance (AMR) calls for the discovery of new antibiotics with innovative modes of action while considering the low toxicity to mammalian cells. This paper proposes a novel strategy for designing antibiotics with selective bacterial toxicity by exploiting the positional differences of electron transport chains (ETC) in bacterial and mammalian cells. The focus is on cytochrome c (cyt C) and its maturation system in E. coli. The catalytic oxidative activity of metallophthalocyanine (MPc), which have a distinctive M-N4 structure, is being investigated. Unlike previous applications based on light-activated reactive oxygen species (ROS) generation, this study exploits the ability of MPcs to oxidize Fe2+ to Fe3+ in cyt C and catalyze the formation of disulfide bonds between cysteine residues to interfere with cyt C maturation, disrupt the bacterial respiratory chain and selectively kills bacteria. In contrast, in mammalian cells, these MPcs are located in the lysosomes and cannot access the ETC in the mitochondria, thus achieving selective bacterial toxicity. Two MPcs that showed effective antibacterial activity in a wound infection model were identified. This study provides a valuable reference for the design of novel antibiotics based on M-N4-based metal complex molecules.

Nanotechnology: “Advancing Material Science and Medicine”

Nanotechnology has been a rapidly growing field of advanced science at the inception of this century. Nanotechnology of advanced materials, polymers, principally revolves around endeavours to plan materials at a sub-atomic level to accomplish alluring properties and applications at a naturally visible level. Nanotechnology can be used for the advancement of technologies, ranging from communication and information, health and medicine, future energy, environment and climate change to transport and cultural heritage, personal protective equipment (PPE), fuels, fuel cells, biosensors, disease sensors etc. Nanomaterials will lead to a new approach to manufacturing materials and devices. Faster computers, advanced pharmaceuticals, controlled drug delivery, biocompatible materials, nerve and tissue repair, crackproof surface coatings, better skin care and protection, more efficient catalysts, better and smaller sensors, even more efficient telecommunication. For example, a low risk solution using antibody modified bismuth nanoparticle, in combination with an X-ray dose equivalent to a chest X-ray specifically, has been shown to kill the common bacterium Pseudomonas aeruginosa in a set up designed to resemble a deep wound in human tissue. Nanosized gold particle could catalyse the oxidation of carbon monoxide better than anything previously known. Heparin functionalized nanoparticles have been use for targeted delivery of anti-malarial drugs. Heparin is abundant and cheap, compared to treatments that involve antibodies, an important consideration, since malaria is most common in developing countries. A bone repairing nano-particle paste has been developed that promises faster repair of fractures and breakages. DNA containing two growth genes is encapsulated inside synthetic calcium phosphate nanoparticles. In a remarkable demonstration of the extreme limits of nanoscale engineering, researchers have used the tip of a scanning tunnelling microscope to cleave and form selected chemical bonds in a complex molecule. Many medicinal and industrial endeavours have seen the use of Nanotechnology. Nanoparticles can attach to SARS COV-2 viruses, disrupting their structure and so kill the virus. These and other more recent advances in nanotechnology will be presented at this conference.