The first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, were successfully accomplished by means of a biomimetic strategy that proceeds through a ...bioinspired 5/6/6/9 tetracyclic intermediate, which mimics the amino ketone form of palhinine D. An early‐stage direct SN2 cyclization to construct the nine‐membered azonane ring minimized the transannular strain that would otherwise be increased by the twisted nature of the isotwistane skeleton. Then, a diastereoselective Diels–Alder reaction of a masked ortho‐benzoquinone using the nine‐membered ring as a steric shielding group furnished a functionalized 6/6/9 tricyclic skeleton and established the desired stereochemistry at the C3, C7, C12, and C15 positions in one step. A thiol‐mediated acyl radical cyclization gave the bioinspired intermediate bearing three differentiated oxygen‐containing functional groups, from which all three total syntheses could be completed in either two or three additional steps.
True to life: Total syntheses of the alkaloids isopalhinine A, palhinine A, and palhinine D were accomplished by means of a biomimetic strategy. Key steps for the synthesis of the core 5/6/6/9 tetracyclic skeleton are 1) an early‐stage direct SN2 cyclization to minimized the transannular strain, 2) a diastereoselective Diels–Alder reaction to furnish 6/6/9 tricyclic structure, and 3) an acyl radical cyclization to complete the 5/6/6/9 tetracyclic core architecture.
P-glycoprotein (P-gp) is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. To date, no drug has ...been approved to inhibit P-gp and restore chemotherapy efficacy. Moreover, majority of the reported inhibitors have high molecular weight and complex structures, making it difficult to understand the basic structural requirement for P-gp inhibition. In this study, two structurally simple, low molecular weight piperine analogs Pip1 and Pip2 were designed and found to better interact with P-gp than piperine in silico. A one step, acid-amine coupling reaction between piperic acid and 6,7-dimethoxytetrahydroisoquinoline or 2-(3,4-dimethoxyphenyl)ethylamine afforded Pip1 and Pip2, respectively. In vitro testing in drug resistant P-gp overexpressing KB (cervical) and SW480 (colon) cancer cells showed that both analogs, when co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance. Moreover, accumulation of P-gp substrate (rhodamine 123) in the resistant cells, a result of alteration of the P-gp efflux, was also observed. These investigations suggest that the natural product analog - Pip1 ((2E,4E)-5-(benzod1,3dioxol-5-yl)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)penta-2,4-dien-1-one) - is superior to piperine and could inhibit P-gp function. Further studies are required to explore the full potential of Pip1 in treating drug resistant cancer.
The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community ...has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Diels‐Alder adducts of masked ortho‐benzoquinone (MOB) normally perform high regio‐ and stereoselectivity and are generated under mild conditions. The advantages of MOB include: (a) Containing ...highly functional moieties: alkene, diene, carbonyl, enone, and dienone; (b) Easily accessible from 2‐methoxyphenol derivatives via oxidative dearomatization, and related 2‐methoxyphenol easily prepared from commercially available starting materials; (c) The Diels‐Alder adducts possessing unique features such as regio‐ and stereoselectivity and at least four contiguous stereogenic centers in one step. Furthermore, related bicyclo2.2.2octenone skeleton can be applied to further complex structure construction by various chemical transformations, such as radical cyclization, oxa‐di‐π‐methane rearrangement, Beckwith‐Dowd rearrangement, hydrogen atom transfer reaction, Cope rearrangement, Wanger‐Meerwein rearrangement, carbonyl‐ene reaction, aldol reaction, ring opening etc. Among these advantages, MOB system is prospected to continue as an important intermediate for total synthesis of natural products.
In this review, we summarize the Diels‐Alder adducts of MOBs, bicyclo2.2.2octenones, as key intermediates for further transformation into complex structures, and their applications in total synthesis of natural products from 2016 to 2021.
Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 ...(10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC50 = 56.4 nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC50 = 3.74–151.4 nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor.
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•A next-generation orally selective type II TRK inhibitor was discovered.•Twenty-nine quinazoline-based analogues were designed and synthesized.•Property-driven strategy guided lead-to-candidate optimization.•39 is a potent TRK inhibitor against both wild-type and mutant TRKs.•39 demonstrated antitumor effectiveness in KM-12 xenograft model.
The study of precision medicine is flourishing in recent decades. Tumor‐agnostic therapy is one of the targeted therapies, which can treat the malignant cells regardless of where they grow. Herein we ...reviewed currently the U.S. FDA‐approved tumor‐agnostic therapies: one monoclonal antibody as a PD‐1 inhibitor called pembrolizumab and four small‐molecule kinase inhibitors, larotrectinib, entrectinib, selpercatinib, and pralsetinib. We also summarized the reported synthetic routes toward three drugs and some developing candidates under clinical trials as tumor‐agnostic therapy.
In this review, we introduced a novel cancer therapy for patients called tumor‐agnostic therapy, including five marketed drugs and several candidates. Pembrolizumab is a PD‐1 inhibitor, whereas larotrectinib, entrectinib, selpercatinib, and pralsetinib are small‐molecule kinase inhibitors. By introducing both marketed and currently developing therapies, we can further comprehend the concept of this breakthrough cancer therapy.
An acyl radical reaction of bicyclo2.2.2octenone to yield either rearranged or cyclized isotwistane products is described. The influence of ring strain on the reaction was demonstrated by ...alternating the sizes of the fused ring in the starting material. DFT calculations showed that the reaction is under thermodynamic control and proceeds via a 5-exo-trig cyclization intermediate, which undergoes either hydrogen-atom transfer (HAT) to give a cyclized product or rearrangement via a twistane intermediate to give a rearranged product.
The inhibition of FMS-like tyrosine kinase 3 (FLT3) activity using small-molecule inhibitors has emerged as a target-based alternative to traditional chemotherapy for the treatment of acute myeloid ...leukemia (AML). In this study, we report the use of structure-based virtual screening (SBVS), a computer-aided drug design technique for the identification of new chemotypes for FLT3 inhibition. For this purpose, homology modeling (HM) of the DFG-in FLT3 structure was carried using two template structures, including PDB ID: 1RJB (DFG-out FLT3 kinase domain) and PDB ID: 3LCD (DFG-in CSF-1 kinase domain). The modeled structure was able to correctly identify known DFG-in (SU11248, CEP-701, and PKC-412) and DFG-out (sorafenib, ABT-869 and AC220) FLT3 inhibitors, in docking studies. The modeled structure was then used to carry out SBVS of an HTS library of 125,000 compounds. The top scoring 97 compounds were tested for FLT3 kinase inhibition, and two hits (BPR056, IC50 = 2.3 and BPR080, IC50 = 10.7 μM) were identified. Molecular dynamics simulation and density functional theory calculation suggest that BPR056 (MW: 325.32; cLogP: 2.48) interacted with FLT3 in a stable manner and could be chemically optimized to realize a drug-like lead in the future.
Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone ...lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC.
In this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts.
Myricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone.
These results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The epigenetic control of gene expression could be affected by addition and/or removal of post-translational modifications such as phosphorylation, acetylation and methylation of histone proteins, as ...well as methylation of DNA (5-methylation on cytosines). Misregulation of these modifications is associated with altered gene expression, resulting in various disease conditions. G9a belongs to the protein lysine methyltransferases that specifically methylates the K9 residue of histone H3, leading to suppression of several tumor suppressor genes. In this review, G9a functions, role in various diseases, structural biology aspects for inhibitor design, structure-activity relationship among the reported inhibitors are discussed which could aid in the design and development of potent G9a inhibitors for cancer treatment in the future.
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