Teriflunomide/leflunomide synergize with chemotherapeutics by decreasing mitochondrial fragmentation via DRP1 in SCLC.

Although up to 80% small cell lung cancer (SCLC) patients' response is good for first-line chemotherapy regimen, most patients develop recurrence of the disease within weeks to months. Here, we report cytostatic effect of leflunomide (Leflu) and teriflunomide (Teri) on SCLC cell proliferation through inhibition of DRP1 phosphorylation at Ser and decreased mitochondrial fragmentation. When administered together, Teri and carboplatin (Carbo) act synergistically to significantly inhibit cell proliferation and DRP1 phosphorylation, reduce abundance of intermediates in pyrimidine pathway, and increase apoptosis and DNA damage.

Total Synthesis and Cytotoxicity Evaluation of Pareitropone and Analogues.

A concise synthesis of pareitropone by oxidative cyclization of a phenolic nitronate is delineated. The use of TMSOTf as an additive to promote the facile formation of a strained norcaradiene intermediate provides convenient access to highly condensed multicyclic tropones in high yields. This synthesis is modular, efficient, and scalable, highlighting the synthetic utility of radical anion coupling reactions in annulation reactions.

Targeting the non-ATP-binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T-cell lymphoma (CTCL).

We describe here for the first time a lipid-binding-domain (LBD) in p38γ mitogen-activated protein kinase (MAPK) involved in the response of T cells to a newly identified inhibitor, CSH71. We describe how CSH71, which binds to both the LBD and the ATP-binding pocket of p38γ, is selectively cytotoxic to CTCL Hut78 cells but spares normal healthy peripheral blood mononuclear (PBMC) cells, and propose possible molecular mechanisms for its action. p38γ is a key player in CTCL development, and we expect that the ability to regulate its expression by specifically targeting the lipid-binding domain will have important clinical relevance.

A Chlorine-Atom-Controlled Terminal-Epoxide-Initiated Bicyclization Cascade Enables a Synthesis of the Potent Cytotoxins Haterumaimides J and K.

Haterumaimide J (hatJ) is reportedly the most cytotoxic member of the lissoclimide family of labdane diterpenoids. The unusual functional group arrangement of hatJ-C18 oxygenation and C2 chlorination-resisted our efforts at synthesis until we adopted an approach based on rarely studied terminal epoxide-based cation-π bicyclizations that is described herein. Using the C2-chlorine atom as a key stereocontrol element and a furan as a nucleophilic terminator, the key structural features of hatJ were rapidly constructed.

Design and Synthesis of New Substituted Pyrazolopyridines with Potent Antiproliferative Activity.

Background: Purine isosteres are often endowed with interesting pharmacological properties, due to their involvement in cellular processes replacing the natural purines. Among these compounds, pyrazolopyridines are under active investigation for potential anticancer properties.

Objectives: Based on previously discovered substituted pyrazolopyridines with promising antiproliferative activity, we designed and synthesized new, suitably substituted analogues aiming to investigate their potential activity and contribute to SAR studies of this class of bioactive compounds.

Preliminary pharmacokinetic study of the anticancer 6BIO in mice using an UHPLC-MS/MS approach.

Indirubins represent a group of natural and synthetic products with bio-activities against numerous human cancer cell lines acting by inhibiting protein kinases. The natural sources of indirubins are plants of Isatis sp., Indigofera sp.

Multi-Kinase Inhibitor with Anti-p38γ Activity in Cutaneous T-Cell Lymphoma.

Current cutaneous T-cell lymphoma (CTCL) therapies are marked by an abbreviated response, subsequent drug resistance, and poor prognosis for patients with advanced disease. An understanding of molecular regulators involved in CTCL is needed to develop effective targeted therapies. One candidate regulator is p38γ, a mitogen-activated protein kinase crucial for malignant T-cell activity and growth.

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides.

The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome.

Plakortinic Acids A and B: Cytotoxic Cycloperoxides with a Bicyclo[4.2.0]octene Unit from Sponges of the Genera Plakortis and Xestospongia.

Plakortinic acids A (2) and B (3), two polyketide endoperoxides with a bicyclo[4.2.0]octene unit, were isolated as minor constituents from the sponge-sponge symbiotic association Plakortis halichondrioides-Xestospongia deweerdtae, along with known epiplakinic acid F (1).

6BIO Enhances Oligonucleotide Activity in Cells: A Potential Combinatorial Anti-androgen Receptor Therapy in Prostate Cancer Cells.

Approximately 15%-25% of men diagnosed with prostate cancer do not survive their disease. The American Cancer Society estimated that for the year 2016 the number of prostate cancer deaths will be 26,120. Thus, there is a critical need for novel approaches to treat this deadly disease.

Synthesis and antiproliferative activity of new pyrazolo[3,4-c]pyridines.

Background: Several pyrazolopyridines possess promising pharmacological activities, mainly attributed to their antagonistic nature towards the natural purines in many biological processes. Cytotoxicity and anticancer potential of this class of compounds is mainly related to induction of apoptotic cell death and inhibition of protein kinases.

Objectives: This prompted us to design, synthesize and study the antiproliferative activity of a number of new 3,7-disubstituted pyrazolo[3,4-c] pyridines.

Natural-Based Indirubins Display Potent Cytotoxicity toward Wild-Type and T315I-Resistant Leukemia Cell Lines.

Drug resistance in chronic myelogenous leukemia (CML) requires the development of new CML chemotherapeutic drugs. Indirubin, a well-known mutikinase inhibitor, is the major active component of "Danggui Longhui Wan", a Chinese traditional medicine used for the treatment of CML symptoms. An in-house collection of indirubin derivatives was screened at 1 μM on wild-type and imatinib-resistant T315I mutant CML cells.

The discovery of new cytotoxic pyrazolopyridine derivatives.

A number of new 3,7-disubstituted pyrazolo[3,4-c]pyridines have been designed and synthesized from suitable 2-aminopyridines. The antiproliferative activity of the derivatives was determined against the pancreatic MIA PaCa-2 and ovarian SCOV3 cancer cell-lines. IC values of the most promising analogue 46 lie in the submicromolar or low micromolar range.

Cinnamon extract reduces VEGF expression via suppressing HIF-1α gene expression and inhibits tumor growth in mice.

Although many anti-VEGF agents are available for cancer treatment, side effects of these agents limit their application for cancer treatment and prevention. Here we studied the potential use of a diet-based agent as an inhibitor for VEGF production. Using a VEGF reporter assay, our data showed that an extract from cinnamon (CE) was a potent inhibitor of VEGF production in human cancer cells and suggested inhibition might be mediated through the suppression of HIF-1α gene expression and protein synthesis.

Site-Selective Aliphatic C-H Chlorination Using N-Chloroamides Enables a Synthesis of Chlorolissoclimide.

Methods for the practical, intermolecular functionalization of aliphatic C-H bonds remain a paramount goal of organic synthesis. Free radical alkane chlorination is an important industrial process for the production of small molecule chloroalkanes from simple hydrocarbons, yet applications to fine chemical synthesis are rare. Herein, we report a site-selective chlorination of aliphatic C-H bonds using readily available N-chloroamides and apply this transformation to a synthesis of chlorolissoclimide, a potently cytotoxic labdane diterpenoid.

Tricyclic Analogues of Epidithiodioxopiperazine Alkaloids with Promising and Antitumor Activity.

Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent antitumor activity. However, their high toxicity and demonstrated interactions with various biological receptors compromises their therapeutic potential. In an effort to mitigate these disadvantages, a short stereocontrolled construction of tricyclic analogues of epidithiodioxopiperazine alkaloids was developed.

Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids.

A unified strategy for enantioselective total synthesis of all stereoisomers of the 2+2 family of quadrigemine alkaloids is reported. In this approach, two enantioselective intramolecular Heck reactions are carried out at the same time on precursors fashioned in four steps from either - or (+)-chimonanthine to form the two critical quaternary carbons of the peripheral cyclotryptamine rings of these products. Useful levels of catalyst control are realized in either desymmetrizing a precursor or controlling diastereoselectivity in elaborating -symmetic intermediates.

Enantioselective synthesis of α-secondary and α-tertiary piperazin-2-ones and piperazines by catalytic asymmetric allylic alkylation.

The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2-ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

A novel synthetic derivative of the natural product berbamine inhibits cell viability and induces apoptosis of human osteosarcoma cells, associated with activation of JNK/AP-1 signaling.

Osteosarcoma is the most common primary bone tumor in children and adolescents. There is a critical need to find more potent drugs for patients with metastatic or recurrent disease. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plants.

General approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors: enantioselective total syntheses of (+)- and (-)-gliocladine C, (+)-leptosin D, (+)-T988C, (+)-bionectin A, and (+)-gliocladin A.

A common strategy for preparing tryptophan-derived epidithiodioxopiperazine (ETP) natural products containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter is reported. This strategy is exemplified by enantioselective total syntheses of four heptacyclic ETP natural products--gliocladine C (6), leptosin D (7), T988C (8), and bionectin A (9)--starting with the di-(tert-butoxycarbonyl) derivative 17 of the trioxopiperazine natural product gliocladin C, which is readily available by enantioselective chemical synthesis. In addition, total syntheses of the enantiomer of gliocladine C (ent-6) and gliocladin A (11), the di(methylthio) congener of bionectin A, are reported.

Amphidinolide B: total synthesis, structural investigation, and biological evaluation.

The total syntheses of amphidinolide B1 and the proposed structure of amphidinolide B2 have been accomplished. Key aspects of this work include the development of a practical, non-transition-metal-mediated method for the construction of the C13-C15 diene, the identification of α-chelation and dipole minimization models for diastereoselective methyl ketone aldol reactions, the discovery of a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy, and the development of a novel late stage method for construction of an allylic epoxide moiety. The originally proposed structure for amphidinolide B2 and diastereomers thereof display potent antitumor activities with IC50 values ranging from 3.

Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells.

Constitutively-activated JAK/Stat3 or Src/Stat3 signaling plays a crucial role in tumor cell survival, proliferation, angiogenesis and immune suppression. Activated JAK/Stat3 or Src/Stat3 has been validated as a promising molecular target for cancer therapy. However, prolonged inhibition of Src family kinases (SFKs) leads to reactivation of signal transducer and activator of transcript 3 (Stat3) and tumor cell survival through altered JAK/Stat3 interaction.