Virtual screening of novel mTOR inhibitors for the potential treatment of human colorectal cancer.

The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 µM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 µM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 µM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.

Quaternary Ammonium Palmitoyl Glycol Chitosan (GCPQ) Loaded with Platinum-Based Anticancer Agents-A Novel Polymer Formulation for Anticancer Therapy.

Quaternary ammonium palmitoyl glycol chitosan (GCPQ) has already shown beneficial drug delivery properties and has been studied as a carrier for anticancer agents. Consequently, we synthesised cytotoxic platinum(IV) conjugates of cisplatin, carboplatin and oxaliplatin by coupling via amide bonds to five GCPQ polymers differing in their degree of palmitoylation and quaternisation. The conjugates were characterised by 1H and 195Pt NMR spectroscopy as well as inductively coupled plasma mass spectrometry (ICP-MS), the latter to determine the amount of platinum(IV) units per GCPQ polymer. Cytotoxicity was evaluated by the MTT assay in three human cancer cell lines (A549, non-small-cell lung carcinoma; CH1/PA-1, ovarian teratocarcinoma; SW480, colon adenocarcinoma). All conjugates displayed a high increase in their cytotoxic activity by factors of up to 286 times compared to their corresponding platinum(IV) complexes and mostly outperformed the respective platinum(II) counterparts by factors of up to 20 times, also taking into account the respective loading of platinum(IV) units per GCPQ polymer. Finally, a biodistribution experiment was performed with an oxaliplatin-based GCPQ conjugate in non-tumour-bearing BALB/c mice revealing an increased accumulation in lung tissue. These findings open promising opportunities for further tumouricidal activity studies especially focusing on lung tissue.

Platinum(IV)-Loaded Degraded Glycol Chitosan as Efficient Platinum(IV) Drug Delivery Platform.

A new class of anticancer prodrugs was designed by combining the cytotoxicity of platinum(IV) complexes and the drug carrier properties of glycol chitosan polymers: Unsymmetrically carboxylated platinum(IV) analogues of cisplatin, carboplatin and oxaliplatin, namely (OC-6-44)-acetatodiammine(3-carboxypropanoato)dichloridoplatinum(IV), (OC-6-44)-acetaodiammine(3-carboxypropanoato)(cyclobutane-1,1-dicarboxylato)platinum(IV) and (OC-6-44)-acetato(3-carboxypropanoato)(1R,2R-cyclohexane-1,2-diamine)oxalatoplatinum(IV) were synthesised and conjugated via amide bonding to degraded glycol chitosan (dGC) polymers with different chain lengths (5, 10, 18 kDa). The 15 conjugates were investigated with 1H and 195Pt NMR spectroscopy, and average amounts of platinum(IV) units per dGC polymer molecule with ICP-MS, revealing a range of 1.3-22.8 platinum(IV) units per dGC molecule. Cytotoxicity was tested with MTT assays in the cancer cell lines A549, CH1/PA-1, SW480 (human) and 4T1 (murine). IC50 values in the low micromolar to nanomolar range were obtained, and higher antiproliferative activity (up to 72 times) was detected with dGC-platinum(IV) conjugates in comparison to platinum(IV) counterparts. The highest cytotoxicity (IC50 of 0.036 ± 0.005 µM) was determined in CH1/PA-1 ovarian teratocarcinoma cells with a cisplatin(IV)-dGC conjugate, which is hence 33 times more potent than the corresponding platinum(IV) complex and twice more potent than cisplatin. Biodistribution studies of an oxaliplatin(IV)-dGC conjugate in non-tumour-bearing Balb/C mice showed an increased accumulation in the lung compared to the unloaded oxaliplatin(IV) analogue, arguing for further activity studies.

Intelligent Reflecting Surface Assisted Secure Transmission in UAV-MIMO Communication Systems.

This paper studies the intelligent reflecting surface (IRS) assisted secure transmission in unmanned aerial vehicle (UAV) communication systems, where the UAV base station, the legitimate receiver, and the malicious eavesdropper in the system are all equipped with multiple antennas. By deploying an IRS on the facade of a building, the UAV base station can be assisted to realize the secure transmission in this multiple-input multiple-output (MIMO) system. In order to maximize the secrecy rate (SR), the transmit precoding (TPC) matrix, artificial noise (AN) matrix, IRS phase shift matrix, and UAV position are jointly optimized subject to the constraints of transmit power limit, unit modulus of IRS phase shift, and maximum moving distance of UAV. Since the problem is non-convex, an alternating optimization (AO) algorithm is proposed to solve it. Specifically, the TPC matrix and AN covariance matrix are derived by the Lagrange dual method. The alternating direction method of multipliers (ADMM), majorization-minimization (MM), and Riemannian manifold gradient (RCG) algorithms are presented, respectively, to solve the IRS phase shift matrix, and then the performance of the three algorithms is compared. Based on the proportional integral (PI) control theory, a secrecy rate gradient (SRG) algorithm is proposed to iteratively search for the UAV position by following the direction of the secrecy rate gradient. The theoretic analysis and simulation results show that our proposed AO algorithm has a good convergence performance and can increase the SR by 40.5% compared with the method without IRS assistance.

Copper-catalyzed direct decarboxylative fluorosulfonylation of aliphatic carboxylic acids.

Sulfonyl fluorides are emerging as key structural motifs in organic synthesis, medicinal chemistry, and materials science. Herein we report two efficient and complementary methods for direct decarboxylative fluorosulfonylation of carboxylic acids by the merging of copper catalysis with different N-centered HAT regents. A wide range of structurally diverse sulfonyl fluorides was readily accessed from primary, secondary, and tertiary carboxylic acids in a single step under mild conditions.

Catalytic Decarboxylative Fluorosulfonylation Enabled by Energy-Transfer-Mediated Photocatalysis.

Sulfonyl fluorides are useful building blocks in a wide array of fields. Herein, we report a catalytic decarboxylative fluorosulfonylation approach for converting abundant aliphatic carboxylic acids to the corresponding sulfonyl fluorides. This transformation is enabled by simple preactivation as aldoxime esters and energy-transfer-mediated photocatalysis. This operationally simple method proceeds with high functional-group tolerance under mild and redox-neutral conditions.

Photoredox-catalyzed aminofluorosulfonylation of unactivated olefins.

The development of efficient approaches to access sulfonyl fluorides is of great significance because of the widespread applications of these structural motifs in many areas, among which the emerging sulfur(vi) fluoride exchange (SuFEx) click chemistry is the most prominent. Here, we report the first three-component aminofluorosulfonylation of unactivated olefins by merging photoredox-catalyzed proton-coupled electron transfer (PCET) activation with radical relay processes. Various aliphatic sulfonyl fluorides featuring a privileged 5-membered heterocyclic core have been efficiently afforded under mild conditions with good functional group tolerance. The synthetic potential of the sulfonyl fluoride products has been examined by diverse transformations including SuFEx reactions and transition metal-catalyzed cross-coupling reactions. Mechanistic studies demonstrate that amidyl radicals, alkyl radicals and sulfonyl radicals are involved in this difunctionalization transformation.

Total Synthesis of Mulberry Diels-Alder-Type Adducts Kuwanons G and H.

Mulberry Diels-Alder-type adducts (MDAAs) are a group of rare natural polyphenols biosynthetically derived from [4 + 2]-cycloaddition of chalcones and dehydroprenylphenols. In this study, kuwanons G (1) and H (2), two bioactive MDAAs with unique dehydroprenylflavonoid dienes, were totally synthesized for the first time in a biomimetic manner. The key features of the convergent route include the use of the Baker-Venkataraman rearrangement, alkylation of ß-diketone, intramolecular cyclization, and Suzuki-Miyaura coupling to achieve the subunit diene.

Organocatalytic enantioselective SN1-type dehydrative nucleophilic substitution: access to bis(indolyl)methanes bearing quaternary carbon stereocenters.

A highly general and straightforward approach to access chiral bis(indolyl)methanes (BIMs) bearing quaternary stereocenters has been realized via enantioconvergent dehydrative nucleophilic substitution. A broad range of 3,3'-, 3,2'- and 3,1'-BIMs were obtained under mild conditions with excellent efficiency and enantioselectivity (80 examples, up to 98% yield and >99 : 1 er). By utilizing racemic 3-indolyl tertiary alcohols as precursors of alkyl electrophiles and indoles as C-H nucleophiles, this organocatalytic strategy avoids pre-activation of substrates and produces water as the only by-product. Mechanistic studies suggest a formal SN1-type pathway enabled by chiral phosphoric acid catalysis. The practicability of the obtained enantioenriched BIMs was further demonstrated by versatile transformation and high antimicrobial activities (3al, MIC: 1 µg mL-1).

Enantioselective Dehydrative γ-Arylation of α-Indolyl Propargylic Alcohols with Phenols: Access to Chiral Tetrasubstituted Allenes and Naphthopyrans.

Herein, we report an enantioselective dehydrative γ-arylation of α-indolyl propargylic alcohols with phenols via organocatalysis, which provides efficient access to chiral tetrasubstituted allenes and naphthopyrans in high yields with excellent regio- and enantioselectivities under mild conditions. This method features the use of cheaply available naphthols/phenols as the C-H aryl source and liberating water as the sole byproduct. Control experiments suggest that the excellent enantioselectivity and remote regioselectivity stem from dual hydrogen-bonding interaction with the chiral phosphoric acid catalyst.

Catalytic Asymmetric Synthesis of Vicinal Tetrasubstituted Diamines via Umpolung Cross-Mannich Reaction of Cyclic Ketimines.

A catalytic asymmetric umpolung cross-Mannich reaction of cyclic ketimines is realized. This protocol provides an efficient methodology for the facile synthesis of chiral vicinal tetrasubstituted diamines in high yields with excellent chemo-, regio-, diastereo-, and enantioselectivities using cinchona-derived bifunctional organocatalysts (85-98% yield, up to >20:1 dr, and >99% ee).

Copper-free Sandmeyer-type Reaction for the Synthesis of Sulfonyl Fluorides.

A copper-free Sandmeyer-type fluorosulfonylation reaction is reported. Utilizing Na2S2O5 and Selectfluor as the sulfur dioxide and fluorine sources, respectively, aryldiazonium salts were transformed into sulfonyl fluorides. The one-pot direct synthesis of sulfonyl fluorides from aromatic amines was also realized via in situ diazotization. The practicality of this method was demonstrated by the broad functional group tolerance, gram-scale synthesis, and late-stage fluorosulfonylation of natural products and pharmaceuticals.

Differentiation and functionalization of remote C-H bonds in adjacent positions.

Site-selective functionalization of C-H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, it is essential to develop strategies to activate C-H bonds that are distal from a functional group. In this context, distinguishing remote C-H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C-H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukaemia agent and hydrocinnamic acid substrates.

Visible-light-promoted radical cross-coupling of para-quinone methides with N-substituted anilines: an efficient approach to 2,2-diarylethylamines.

An efficient protocol to access 2,2-diarylethylamines via visible-light-promoted radical reactions of para-quinone methides (p-QMs) with N-alkyl anilines has been disclosed. These reactions feature metal-free, redox-neutral, and mild reaction conditions with wide functional group compatibility.

Construction of Sulfonyl Phthalides via Copper-Catalyzed Oxysulfonylation of 2-Vinylbenzoic Acids with Sodium Sulfinates.

Copper-catalyzed difunctionalization of 2-vinylbenzoic acids with sodium sulfinates to construct substituted lactones has been realized. This protocol employs inexpensive CuCl2 as the catalyst, di-tert-butyl peroxide or O2 as the terminal oxidant, and readily available sodium sulfinates as sulfonylation reagents. High functional group tolerance and excellent yields were demonstrated by the efficient preparation of a wide range of γ-sulfonylated phthalides.

Reversing conventional site-selectivity in C(sp3)-H bond activation.

One of the core barriers to developing C-H activation reactions is the ability to distinguish between multiple C-H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp2)-H bonds have been selectively activated in the presence of proximate ones. Yet achieving such unconventional site selectivity with C(sp3)-H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid-derived directing group and a 2-pyridone ligand that enables the preferential activation of the distal γ-C(sp3)-H bond over the proximate ß-C(sp3)-H bonds for a wide range of alcohol-derived substrates. A competition experiment between the five- and six-membered cyclopalladation step, as well as kinetic experiments, demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp3)-H activation.

Visible-Light-Mediated Decarboxylative Benzylation of Imines with Arylacetic Acids.

A straightforward method for the visible-light-mediated decarboxylative benzylation of imines is reported. The key feature of this method is the use of simple primary, secondary, and tertiary arylacetic acids as precursors of benzyl radicals, enabling the facile benzylation of a variety of imines under mild conditions. A variety of structurally diverse ß-arylethylamines (37 examples) was accessed using this method.

Nickel-catalyzed direct C-H bond sulfenylation of acylhydrazines.

A Ni-catalyzed direct C-H bond sulfenylation of acylhydrazines was developed. The reaction used N-(pyridinyl)hydrazine as the bidentate-directing group, which can be smoothly removed through reductive N-N cleavage. This system can bear various important functional groups, providing an efficient route for the preparation of diverse diaryl sulfides.

Copper-catalyzed aerobic decarboxylative coupling between cyclic α-amino acids and diverse C-H nucleophiles with low catalyst loading.

An aerobic decarboxylative cross-coupling of α-amino acids with diverse C-H nucleophiles has been realized using Cu2(OH)2CO3 (1 mol%) as the catalyst under air. This protocol enables highly efficient formation of various C(sp3)-C(sp3), C(sp3)-C(sp2) and C(sp3)-C(sp) bonds under simple conditions without the use of any ligand or extra oxidant, providing a practical approach to numerous nitrogen-containing compounds in good to excellent yields. The efficiency and practicability were also demonstrated by the gram-scale experiment and three-step synthesis of a Rad51 inhibitor.

Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors.

Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kß/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.