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1.
J Org Chem ; 89(9): 6230-6237, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38629386

ABSTRACT

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. This work is discussed in the context of total syntheses of the tropoloisoquinoline alkaloids. Also included are the preparation of several congeners and a brief description of their biological activities.


Subject(s)
Antineoplastic Agents , Humans , Molecular Structure , Cyclization , Cell Line, Tumor , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , Oxidation-Reduction
2.
FEBS Lett ; 595(20): 2570-2592, 2021 10.
Article in English | MEDLINE | ID: mdl-34455585

ABSTRACT

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. Our findings characterize novel mechanisms of gene regulation in T lymphoma cells and validate the use of computational screening techniques to identify inhibitors for therapeutic development.


Subject(s)
Adenosine Triphosphate/metabolism , Lymphoma, T-Cell, Cutaneous/metabolism , Mitogen-Activated Protein Kinase 12/metabolism , Skin Neoplasms/metabolism , Antineoplastic Agents/therapeutic use , Gene Expression Regulation, Neoplastic , Humans , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/genetics , Signal Transduction , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics
3.
Med Chem ; 16(2): 176-191, 2020.
Article in English | MEDLINE | ID: mdl-30799794

ABSTRACT

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. METHODS: The new compounds were synthesized using suitably substituted 2-amino-4-picolines, which upon ring-closure provided substituted pyrazolo[3,4-c] pyridine-5-carbonitriles that served as key intermediates for the preparation of the target 3,5,7 trisubstituted derivatives. The antiproliferative activity of 31 new target derivatives was evaluated against three cancer cell lines (MIA PaCa-2, PC-3 and SCOV3), whereas cell-cycle perturbations of exponentially growing PC-3 cells, using three selected derivatives were also performed. RESULTS: Eight compounds displayed IC50 values in the low µM range, allowing the extraction of interesting SAR's. Two of the most potent compounds against all cell lines share a common pattern, by accumulating cells at the G0/G1 phase. From this project, a new carboxamidine-substituted hit has emerged. CONCLUSION: Among the new compounds, those possessing the 3-phenylpyrazolo[3,4-c]pyridine scaffold, proved to be worth investigating and the majority of them showed strong cytotoxic activity against all cell lines, with IC50 values ranging from 0.87-4.3 µM. A carboxamidine analogue that resulted from the synthetic procedure, proved to be highly active against the cancer cells and could be considered as a useful lead for further optimization.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Pyridines/chemical synthesis , Pyridines/pharmacology , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chemistry Techniques, Synthetic , Humans , Pyridines/chemistry
4.
J Am Chem Soc ; 141(23): 9202-9206, 2019 06 12.
Article in English | MEDLINE | ID: mdl-31129963

ABSTRACT

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. The 18-step stereoselective synthesis features applications of chiral pool starting materials, and catalyst-, substrate-, and auxiliary-based stereocontrol. Access to hatJ and its acetylated congener hatK permitted their biological evaluation against aggressive human cancer cell lines.


Subject(s)
Chlorine/chemistry , Diterpenes/chemical synthesis , Diterpenes/toxicity , Epoxy Compounds/chemistry , Cyclization , Models, Molecular , Molecular Structure
5.
J Pharm Biomed Anal ; 164: 317-325, 2019 Feb 05.
Article in English | MEDLINE | ID: mdl-30412805

ABSTRACT

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., and Polygonum sp., recombinant bacteria, mammalian urine and some marine mollusks. Specifically, the halogenated derivative 6-bromo indirubin-3'-oxime (6BIO) possesses increased selectivity against GSK-3. However, to our knowledge, no analytical method to determine 6BIO in biological fluids has been developed till now. Therefore, a rapid, sensitive and high throughput UHPLC-MS/MS methods were developed and validated to evaluate the concentrations of 6BIO in mice plasma. Plasma samples were pre-treated by protein precipation using cold mixture of methanol: acetonitrile (9:1, v/v) and separations were carried out on a Hypersil Gold C18 column (50 × 2.1 mm i.d.; 1.9 µm p.s.) using 0.1% acetic acid and methanol as mobile phase at a flow rate of 500 mL/min in a gradient mode. For quantitation, a hybrid LTQ-Orbitrap MS equipped with an electro-spray ionization source was used applying a selected reaction monitoring (SRM) option. The monitored transitions were m/z 354.0 → 324.0 for 6BIO and 297.1 → 282.1 for afromorsin (used as the internal standard) in the negative mode. Following the EMA, ICH and FDA guidelines for validation of analytical procedures, the assay method was fully validated in terms of selectivity, linearity, recovery, matrix effect, accuracy, precision, stability, and robustness. The validated methods were successfully applied to the pharmacokinetic studies of 6BIO following an oral administration to mice at the dose of 50 mg/kg. The results indicated that 6BIO possesses a Tmax of 30 min, a half-life of 1 h, and low plasma bioavailability.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Glycogen Synthase Kinase 3/antagonists & inhibitors , Indoles/pharmacokinetics , Oximes/pharmacokinetics , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Biological Availability , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Drug Evaluation, Preclinical , Indoles/administration & dosage , Mice , Oximes/administration & dosage , Reference Standards , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization/instrumentation , Tandem Mass Spectrometry/instrumentation
6.
J Invest Dermatol ; 138(11): 2377-2387, 2018 11.
Article in English | MEDLINE | ID: mdl-29758280

ABSTRACT

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. p38γ gene expression is selectively increased in CTCL patient samples and cell lines but not in healthy T cells. In addition, gene silencing of p38γ reduced CTCL cell viability, showing a key role in CTCL pathogenesis. Screening p38γ inhibitors is critical for understanding the mechanism of CTCL tumorigenesis and developing therapeutic applications. We prioritized a potent p38γ inhibitor (F7, also known as PIK75) through a high-throughput kinase inhibitor screen. At nanomolar concentrations, PIK75, a multiple kinase inhibitor, selectively killed CD4+ malignant CTCL cells but spared healthy CD4+ cells; induced significant reduction of tumor size in mouse xenografts; and effectively inhibited p38γ enzymatic activity and phosphorylation of its substrate, DLGH1, in CTCL cells and mouse xenografts. Here, we report that PIK75 has a potential clinical application to serve as a scaffold molecule for the development of a more selective p38γ inhibitor.


Subject(s)
Antineoplastic Agents/therapeutic use , CD4-Positive T-Lymphocytes/physiology , Lymphoma, T-Cell, Cutaneous/drug therapy , Mitogen-Activated Protein Kinase 12/metabolism , Protein Kinase Inhibitors/therapeutic use , Skin Neoplasms/drug therapy , Animals , CD4-Positive T-Lymphocytes/drug effects , Carcinogenesis , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mitogen-Activated Protein Kinase 12/antagonists & inhibitors , Mitogen-Activated Protein Kinase 12/genetics , Molecular Targeted Therapy , Protein Kinase Inhibitors/pharmacology , RNA, Small Interfering/genetics , Tumor Burden , Tumor Cells, Cultured , Up-Regulation , Xenograft Model Antitumor Assays
7.
Nat Chem ; 9(11): 1140-1149, 2017 11.
Article in English | MEDLINE | ID: mdl-29064494

ABSTRACT

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. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.


Subject(s)
Diterpenes/chemical synthesis , Diterpenes/pharmacology , Protein Biosynthesis/drug effects , Succinimides/chemical synthesis , Succinimides/pharmacology , Animals , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Biological Products/chemical synthesis , Biological Products/chemistry , Biological Products/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Diterpenes/chemistry , Drug Screening Assays, Antitumor , Eukaryotic Initiation Factors/antagonists & inhibitors , Eukaryotic Initiation Factors/metabolism , Humans , Mice , Models, Molecular , Molecular Conformation , Peptides, Cyclic , Succinimides/chemistry
8.
Org Lett ; 19(6): 1486-1489, 2017 03 17.
Article in English | MEDLINE | ID: mdl-28272898

ABSTRACT

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). The structures of the mixture of two inseparable compounds were determined by spectroscopic analysis. Screening for cytotoxic activity of the mixture against two human tumor cell lines revealed that these compounds are very active at sub-micromolar concentration.


Subject(s)
Peroxides/chemistry , Plakortis/chemistry , Polyketides/chemistry , Xestospongia/chemistry , Animals , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor/methods , Humans , Peroxides/isolation & purification , Peroxides/pharmacology , Polyketides/isolation & purification , Polyketides/pharmacology , Stereoisomerism
9.
Mol Ther ; 25(1): 79-91, 2017 01 04.
Article in English | MEDLINE | ID: mdl-28129131

ABSTRACT

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. Using high-throughput small-molecule screening, we found that the small molecule 6-bromo-indirubin-3'-oxime (6BIO) significantly improves the targeting of antisense oligonucleotides (ASOs) delivered by gymnosis (i.e., in the absence of any transfection reagents) in both the cell cytoplasm and the nucleus. Furthermore, as a single agent, 6BIO had the unexpected ability to simultaneously downregulate androgen receptor (AR) expression and AR signaling in prostate cancer cells. This includes downregulating levels of the AR-V7, a drug-resistance-related AR splice variant that is important in the progression of prostate cancer. Combining 6BIO and an anti-AR oligonucleotide (AR-ASO) can augment the downregulation of AR expression. We also demonstrated that 6BIO enhances ASO function and represses AR expression through the inhibition of the two main glycogen synthase kinase 3 (GSK-3) isoforms: GSK-3α and GSK-3ß activity. Our findings provide a rationale for the use of 6BIO as a single agent or as part of a combinatorial ASO-based therapy in the treatment of human prostate cancer.


Subject(s)
Androgen Receptor Antagonists/pharmacology , Antineoplastic Agents/pharmacology , Indoles/pharmacology , Oligonucleotides/pharmacology , Oximes/pharmacology , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Cell Line, Tumor , Cytoplasm , Drug Synergism , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Male , MicroRNAs/genetics , MicroRNAs/pharmacology , Oligonucleotides/genetics , Oncogenes/genetics , Prostatic Neoplasms/genetics , RNA Splicing , Receptors, Androgen/genetics , Signal Transduction
10.
Mol Carcinog ; 56(2): 436-446, 2017 02.
Article in English | MEDLINE | ID: mdl-27253180

ABSTRACT

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. Furthermore, CE treatment was found to inhibit expression and phosphorylation of STAT3 and AKT, which are key factors in the regulation of HIF-1α expression, and significantly reduce angiogenesis potential of cancer cells by migration assay. Consistent with these results, we observed significant suppression of VEGF expression, blood vessel formation, and tumor growth in a human ovarian tumor model in mice treated with CE. Cinnamaldehyde, a major component in cinnamon, was identified as one active component in CE that inhibits VEGF expression. Taken together, our findings provide a novel mechanism underlying anti-angiogenic and anti-tumor actions of CE and support the potential use of CE in cancer prevention and treatment. © 2016 Wiley Periodicals, Inc.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Cinnamomum zeylanicum/chemistry , Gene Expression Regulation, Neoplastic/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Ovarian Neoplasms/drug therapy , Ovary/drug effects , Vascular Endothelial Growth Factor A/genetics , Animals , Antineoplastic Agents, Phytogenic/chemistry , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/analysis , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mice, SCID , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Ovary/blood supply , Ovary/metabolism , Ovary/pathology , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Vascular Endothelial Growth Factor A/analysis , Vascular Endothelial Growth Factor A/metabolism
11.
Med Chem ; 2016 Dec 13.
Article in English | MEDLINE | ID: mdl-27978787

ABSTRACT

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. METHODS: 2-amino-3-nitro-4-picoline was suitably modified and ring closed to provide 7-chloropyrazolo[3,4-c]pyridine. Iodination of this derivative was followed by the insertion of 3-aryl substituents via Suzuki coupling and aromatic nucleophilic substitution of the 7-chloro group by the appropriate amines. The antiproliferative activity of the target compounds was evaluated against A2058 melanoma, DU145 and PC3 prostate cancer cell lines. Flow cytometric analysis of DNA content for selected compounds was performed, after incubation of exponentially growing PC-3 cells. RESULTS: Eighteen new pyrazolopyridines have been synthesized and fully characterized. Among them, the majority of the 3-(3-fluorophenyl) derivatives exhibit interesting antiproliferative activity, with IC50 values in the range of 3.0-16.0 µM and present reasonable SARs. Cell-cycle perturbations revealed that the most active derivative 12a blocks cells at the S phase. CONCLUSION: 3-(3-Fluorophenyl)-7-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-c]pyridine (12a) and the corresponding 1-(4-methoxybenzyl)- analogue (11a) possess interesting antiproliferative activity against all cell lines tested. Derivatives bearing this substitution pattern can be considered as useful leads for further biological evaluation.

12.
J Nat Prod ; 79(10): 2464-2471, 2016 10 28.
Article in English | MEDLINE | ID: mdl-27726390

ABSTRACT

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. Herein are reported that only 15 analogues of the natural 6-bromoindirubin displayed potent cytotoxicity in the submicromolar range. Kinase assays in vitro show that eight out of the 15 active molecules strongly inhibited both c-Src and Abl oncogenic kinases in the nanomolar range. Most importantly, these eight molecules blocked the activity of T315I mutant Abl kinase at the submicromolar level and with analogue 22 exhibiting inhibitory activity at the low nanomolar range. Docking calculations suggested that active indirubins might inhibit T315I Abl kinase through an unprecedented binding to both active and Src-like inactive conformations. Analogue 22 is the first derivative of a natural product identified as an inhibitor of wild-type and imatinib-resistant T315I mutant Abl kinases.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , src-Family Kinases/metabolism , Apoptosis/drug effects , Benzamides/pharmacology , CSK Tyrosine-Protein Kinase , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Resistance, Neoplasm/drug effects , Humans , Imatinib Mesylate/pharmacology , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Piperazines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology
13.
Bioorg Med Chem Lett ; 26(21): 5229-5233, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27720292

ABSTRACT

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. IC50 values of the most promising analogue 46 lie in the submicromolar or low micromolar range. Furthermore, compound 46 shows similar inhibitory activities against DU145, A2058 and PC-3 cancer cells, blocks the cell cycle at the G0/G1 phase and induce apoptosis, as determined by the appearance of apoptotic nuclei.


Subject(s)
Pyrazoles/chemistry , Pyridines/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Discovery , Humans , Magnetic Resonance Spectroscopy , Pyrazoles/pharmacology , Pyridines/pharmacology
14.
J Am Chem Soc ; 138(2): 696-702, 2016 Jan 20.
Article in English | MEDLINE | ID: mdl-26694767

ABSTRACT

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. These reactions deliver alkyl chlorides in useful chemical yields with substrate as the limiting reagent. Notably, this approach tolerates substrate unsaturation that normally poses major challenges in chemoselective, aliphatic C-H functionalization. The sterically and electronically dictated site selectivities of the C-H chlorination are among the most selective alkane functionalizations known, providing a unique tool for chemical synthesis. The short synthesis of chlorolissoclimide features a high yielding, gram-scale radical C-H chlorination of sclareolide and a three-step/two-pot process for the introduction of the ß-hydroxysuccinimide that is salient to all the lissoclimides and haterumaimides. Preliminary assays indicate that chlorolissoclimide and analogues are moderately active against aggressive melanoma and prostate cancer cell lines.


Subject(s)
Chlorine/chemistry , Diterpenes/chemistry , Succinimides/chemistry , Carbon/chemistry , Hydrogen/chemistry
15.
Chem Sci ; 6: 4451-4457, 2015.
Article in English | MEDLINE | ID: mdl-26301062

ABSTRACT

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. Evaluation of a small library of such structures against two invasive cancer cell lines defined initial structure-activity relationships (SAR), which identified 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine 3c and related structures as particularly promising antitumor agents. ETP alkaloid analogue 3c exhibits low nanomolar activity against both solid and blood tumors in vitro. In addition, 3c significantly suppresses tumor growth in mouse xenograft models of melanoma and lung cancer, without obvious signs of toxicity, following either intraperitoneal (IP) or oral administration. The short synthesis of molecules in this series will enable future mechanistic and translational studies of these structurally novel and highly promising clinical antitumor candidates.

16.
Tetrahedron ; 71(37): 6424-6436, 2015 Sep 16.
Article in English | MEDLINE | ID: mdl-26257440

ABSTRACT

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 meso- 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 meso precursor or controlling diastereoselectivity in elaborating C2-symmetic intermediates. None of the synthetic quadrigemines are identical with alkaloids isolated previously and referred to as quadrigemines A and E. In addition, we report improvements in our previous total syntheses of (+)- or (-)-quadrigemine C that shortened the synthetic sequence to 10 steps and provided these products in 2.2% overall yield from tryptamine.

17.
Angew Chem Int Ed Engl ; 54(1): 179-83, 2015 Jan 02.
Article in English | MEDLINE | ID: mdl-25382664

ABSTRACT

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.


Subject(s)
Allyl Compounds/chemistry , Palladium/chemistry , Piperazines/chemical synthesis , Alkylation , Catalysis , Piperazine , Piperazines/chemistry , Stereoisomerism
19.
PLoS One ; 9(4): e94443, 2014.
Article in English | MEDLINE | ID: mdl-24732116

ABSTRACT

Glioblastoma (GBM) is the most common primary brain tumor, accounting for approximately 40% of all central nervous system malignancies. Despite standard treatment consisting of surgical resection, radiotherapy and/or chemotherapy, the prognosis for GBM is poor; with a median survival of 14.6 months. The cancer stem cell or cancer-initiating cell model has provided a new paradigm for understanding development and recurrence of GBM following treatment. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plant, and along with its derivatives, has been shown to exhibit antitumor activity in several cancers. Here, we reported that a novel synthetic Berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of cancer stem-like cells (CSCs) in a time- and dose-dependent manner when the CSCs from four GBM patients (PBT003, PBT008, PBT022, and PBT030) were cultured. These CSCs grew in neurospheres and expressed CD133 and nestin as markers. Treatment with BBMD3 destroyed the neurosphere morphology, and led to the induction of apoptosis in the CSCs. Induction of apoptosis in these CSCs is dependent upon activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). MicroRNA-4284 (miR-4284) was shown to be over-expressed about 4-fold in the CSCs following BBMD3 treatment. Furthermore, transfection of synthetic anti-sense oligonucleotide against human miR-4284 partially blocked the anticancer effects of BBMD3 on the GBM derived CSCs. BBMD3 also increased phosphorylation of the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in an increase expression of phosphorylated c-Jun and total c-Fos; the major components of transcriptional factor AP-1. The JNK-c-Jun/AP-1 signaling pathway plays an important role in the induction of apoptosis in response to UV irradiation and some drug treatments. Targeting glioblastoma stem-like cells with BBMD3 is therefore novel, and may have promise as an effective therapeutic strategy for treating GBM patients.


Subject(s)
Apoptosis/drug effects , Benzylisoquinolines/pharmacology , Glioblastoma/pathology , JNK Mitogen-Activated Protein Kinases/metabolism , MicroRNAs/metabolism , Neoplastic Stem Cells/pathology , Transcription Factor AP-1/metabolism , Up-Regulation/drug effects , Benzylisoquinolines/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/enzymology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Caspase 3/metabolism , Cell Line, Tumor , Cell Shape/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/drug therapy , Glioblastoma/enzymology , Glioblastoma/genetics , Humans , MicroRNAs/genetics , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neural Stem Cells/drug effects , Neural Stem Cells/metabolism , Neural Stem Cells/pathology , Phosphorylation/drug effects , Poly(ADP-ribose) Polymerases/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Spheroids, Cellular/drug effects , Spheroids, Cellular/pathology , Up-Regulation/genetics
20.
Cancer Biol Ther ; 14(11): 1024-31, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24025361

ABSTRACT

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. BBM and its derivatives have been shown to have antitumor effects in several cancers. Here, we report that a novel synthetic berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of G292, KHOS, and MG-63 human osteosarcoma cells. Induction of apoptosis in these tumor cells depends on activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). Since pan-caspase inhibitor (Z-VAD-FMK) and caspase-9 inhibitor (Z-LEHD-FMK) could block the cleavage of PARP, the apoptosis induced by BBMD3 is through intrinsic signaling pathway. BBMD3 increased phosphorylation of c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in increase of phosphorylated c-Jun and total c-Fos, the major components of transcriptional factor AP-1. JNK inhibitor could partially suppress antitumor effect of BBMD3 on osteosarcoma cells. BBMD3 increased the production of reactive oxygen species (ROS) and ROS scavenger, N-acetylcysteine (NAC), could block the phosphorylation of JNK and c-Jun induced by BBMD3. BBMD3 increased the expression of the pro-apototic gene Bad, associated with apoptosis induction. Finally, BBMD3 also decreased the expression of cyclin D1 and D2, the positive cell cycle regulators, which is correlated with growth inhibition in osteosarcoma cells. Collectively, these findings indicate that BBMD3 is a potentially promising drug for the treatment of human osteosarcoma.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzylisoquinolines/pharmacology , Bone Neoplasms/pathology , JNK Mitogen-Activated Protein Kinases/physiology , Osteosarcoma/pathology , Transcription Factor AP-1/physiology , Bone Neoplasms/drug therapy , Bone Neoplasms/metabolism , Caspase 3/metabolism , Cell Line, Tumor/drug effects , Cell Survival/drug effects , Cyclin D1/metabolism , Cyclin D2/metabolism , Humans , Osteosarcoma/drug therapy , Osteosarcoma/metabolism , Phosphorylation , Reactive Oxygen Species/metabolism , Signal Transduction
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