Late-stage modification of complex drug: Base-controlled Pd-catalyzed regioselective synthesis and bioactivity of arylated osimertinibs.

Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed C─H arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (K2CO3) promoted the arylation of acrylamide terminal C(sp2)-H, affording 34 derivatives. Conversely, sodium tert-butoxide (t-BuONa) mediated the aryl C(sp2)-H arylation of the indole C2 position, providing 27 derivatives. The derivative 3r containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFRT790M/L858R and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a "one substrate-multi reactions-multiple products" strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.

BL-918, a small-molecule activator of ULK1, induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy.

Amyotrophic lateral sclerosis (ALS) is one of the most common fatal neurodegenerative diseases in adults. ALS pathogenesis is associated with toxic SOD1 aggregates generated by mutant SOD1. Since autophagy is responsible for the clearance of toxic protein aggregates including SOD1 aggregates, autophagy induction has been considered as a potential strategy for treating ALS. Autophagic signaling is initiated by unc-51 like autophagy activating kinase 1 (ULK1) complex. We previously identified that BL-918 as a specific ULK1 activator, which exerted cytoprotective effect against Parkinson's disease in vitro and in vivo. In this study we investigated whether BL-918 exerted a therapeutic effect against ALS, and characterized its pharmacokinetic profile in rats. In hSODG93A-NSC34 cells, treatment with BL-918 (5, 10 µM) dose-dependently induced ULK1-dependent autophagy, and eliminated toxic SOD1 aggregates. In SODG93A mice, administration of BL-918 (40, 80 mg/kg, b.i.d., i.g.) dose-dependently prolonged lifespan and improved the motor function, and enhanced the clearance of SOD1 aggregates in spinal cord and cerebral cortex through inducing autophagy. In the pharmacokinetic study conducted in rats, we found BL-918 and its 2 metabolites (M8 and M10) present in spinal cord and brain; after intragastric and intravenous administration, BL-918 reached the highest blood concentration compared to M8 and M10. Collectively, ULK1 activator BL-918 displays a therapeutic potential on ALS through inducing cytoprotective autophagy. This study provides a further clue for autophagic dysfunction in ALS pathogenesis.

Deep Learning Promotes the Screening of Natural Products with Potential Microtubule Inhibition Activity.

Natural microtubule inhibitors, such as paclitaxel and ixabepilone, are key sources of novel medications, which have a considerable influence on anti-tumor chemotherapy. Natural product chemists have been encouraged to create novel methodologies for screening the new generation of microtubule inhibitors from the enormous natural product library. There have been major advancements in the use of artificial intelligence in medication discovery recently. Deep learning algorithms, in particular, have shown promise in terms of swiftly screening effective leads from huge compound libraries and producing novel compounds with desirable features. We used a deep neural network to search for potent ß-microtubule inhibitors in natural goods. Eleutherobin, bruceine D (BD), and phorbol 12-myristate 13-acetate (PMA) are three highly effective natural compounds that have been found as ß-microtubule inhibitors. In conclusion, this paper describes the use of deep learning to screen for effective ß-microtubule inhibitors. This research also demonstrates the promising possibility of employing deep learning to develop drugs from natural products for a wider range of disorders.

Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of N-Aryltacrine Derivatives.

A new series of N-aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald-Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, N-(4-(trifluoromethyl)phenyl)-tacrine (3g) and N-(4-methoxypyridin-2-yl)-tacrine (3o) showed the most potent activity against AChE (IC50 values of 1.77 and 1.48 µM, respectively). The anti-AChE activity of 3g and 3o was 3.5 times more than that of tacrine (IC50 value of 5.16 µM). Compound 3o also displayed anti-BuChE activity with an IC50 value of 19.00 µM. Cell-based assays against HepG2 and SH-SY5Y cell lines revealed that 3o had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in SH-SY5Y cells. The advantages including synthetic accessibility, high potency, low toxicity, and adjunctive neuroprotective activity make compound 3o a new promising multifunctional candidate for the treatment of Alzheimer's disease.

Isolation, Structure Elucidation, Semi-Synthesis, and Structural Modification of C19-Diterpenoid Alkaloids from Aconitum apetalum and Their Neuroprotective Activities.

Five new aconitine-type C19-diterpenoid alkaloids, apetalrines A-E (1-5), were isolated from Aconitum apetalum. Their structures were determined by analysis of 1D and 2D NMR, IR, and HRESIMS data. Semisynthesis of apetalrine B (2) from its parent compound aconorine was achieved to confirm the structure proposed. Twenty derivatives of 2 (11a-11l, 12a, 12b, 12d, 12e, 12j, 12k, 12m, 12n) were synthesized via a unified approach relying on simple coupling reactions. The evaluation of neuroprotective effects of compounds (1-5, 11b, 11c, 11f-11i, 12a, 12b, 12d, 12e, 12k, 12m, 12n) with low cytotoxicity revealed compound 2 to exhibit good neuroprotective effects in H2O2-treated SH-SY5Y cells at a concentration of 50 µM. A series of studies using flow cytometry, staining, and Western blotting on 2 indicated that its neuroprotective effects may arise from inhibiting cell apoptosis.

Diarylheptanoid: A privileged structure in drug discovery.

Privileged structures are widely used in the process of drug design, and provide an effective template in medicinal chemistry. Diarylheptanoids are a class of structurally distinctive compounds with a wide variety of bioactivity, raising keenly interest in the past decades. Turmeric is a golden spice from the rhizome of the plant Curcuma longa, used for food preparations and giving color since ancient times. Curcumin, obtained from turmeric, has showed widely biological abilities with low toxicity in recent studied. Thus, a spice originally common in the kitchen has recently broadened its application to the clinic. This review aims to highlight diarylheptanoid as a privileged scaffold in drug discovery. In this review, we summarized diverse biological and pharmacological effects of diarylheptanoids and explored the therapeutic application and development of diet based on their structure.

Five New Diterpenoids from the Seeds of Euphorbia lathyris.

A new premyrsinane-type diterpenoid, premylanin (1), and four new lathyrane-type diterpenoids named Euphorbia Factors L30 -L33 (2-5) were isolated from the seeds of Euphorbia lathyris, together with thirteen known ones (6-18). Their structures were elucidated through spectroscopic analyses, including IR, UV, HR-ESI-MS, 1D- and 2D-NMR. The cytotoxicities of compounds 1-4 and 6-18 against HCT116, MCF-7, 786-0, HepG2 cell lines were evaluated, and compound 13 exhibited considerable cytotoxic activities with an IC50 values of 6.44, 8.43, 15.3, 9.32 µm, respectively.

Cytotoxic Lathyrane-Type Diterpenes from Seeds of Euphorbia lathyris.

We isolated two new lathyrane-type diterpenes L27 (1) and L28 (2) along with seven known compounds (3-9) from the seeds of Euphorbia lathyris. These compounds were identified by NMR, high-resolution electrospray ionisation (HR-ESI)-MS as well as IR spectroscopy. Compounds 1 and 2 were assigned NMR spectrums with 1H-NMR, 13C-NMR, distortionless enhancement by polarization (DEPT), correlation spectroscopy (COSY), heteronuclear multiple quantum coherence (HMQC), heteronuclear multiple bond connectivity (HMBC) and nuclear Overhauser effect spectroscopy (NOESY). Stereo configuration of 1 and 2 were confirmed by comprehensive interpretation of their nuclear Overhauser effect (NOE) relationship and showed they were first natural lathyrane-type diterpenes possessing α-configuration substitutes at C-3. Cytotoxicity assay of isolated compounds were evaluated against breast cancer cell lines MCF-7 or MDA-MB-231, 786-0 and liver cancer cell lines HepG2. As a result, Euphorbia factor L28 (2) showed strongly cytotoxicity to the 786-0 and HepG2 cell lines, with an IC50 value of 9.43 and 13.22 µM, respectively, which preliminarily suggested that the configuration of lathyrane-type diterpene at C-3 has a significant effect on its bioactivity.