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1.
Bioorg Chem ; 141: 106845, 2023 12.
Article in English | MEDLINE | ID: mdl-37797453

ABSTRACT

Blapspirooxindoles A-C (1-3), three novel spirooxindole alkaloids with a unique spiro[chromane-4,3'-indoline]-2,2'-dione motif, blapcumaranons A and B (4 and 5), two new 2-cumaranon derivatives, blapoxindoles A-J (6-15), ten new oxindole alkaloid derivatives, along with one known compound (16), were isolated from the whole bodies of Blaps japanensis. Their structures including absolute configurations were determined by using spectroscopic, X-ray crystallographic, and computational methods. Compounds 1-11 and 13 exist as racemic mixtures in nature, and their (-)- and (+)-antipodes were separated by chiral HPLC. Biological evaluations of these compounds were determined with multiple assays including anti-tumor, anti-inflammatory, and renal protection activities in vitro. Several compounds displayed effective activity in one or more assays.


Subject(s)
Alkaloids , Antineoplastic Agents , Coleoptera , Neoplasms , Animals , Coleoptera/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Alkaloids/pharmacology , Oxindoles/pharmacology , Molecular Structure
2.
Phytochemistry ; 211: 113699, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37105351

ABSTRACT

(+) and (-)-Eugenilones A-K, 11 pairs of undescribed enantiomeric sesquiterpenoids, together with three undescribed biogenetically related members eugenilones L-N, were discovered from the fruits of Eugenia uniflora Linn. (Myrtaceae). Structurally, eugenilones A-D were four caged sesquiterpenoids featuring 9,10-dioxatricyclo [6.2.2.02,7]dodecane, 11-oxatricyclo [5.3.1.03,8]undecane, and tricyclo [4.4.0.02,8]decane cores, respectively. Eugenilones E-K were eudesmane-type sesquiterpenoids, while eugenilones L-N were epoxy germacrane-type sesquiterpenoids. Notably, eugenilones A-K were efficiently resolved by chiral HPLC to give 11 pairs of optically pure enantiomers. The structures and absolute configurations of eugenilones A-N were determined through spectroscopic analyses, X-ray crystallography, and ECD calculations. The putative biosynthetic pathways for these undescribed isolates were proposed. Moreover, eugenilones A and E exhibited significant anti-inflammatory effects by inhibiting LPS-stimulated NO overproduction in RAW264.7 cells (IC50 values of 4.89 ± 0.37 µM and 20.89 ± 1.49 µM, respectively) and TNF-α-induced NF-κB activation in HEK293 cells (IC50 values of 10.97 ± 1.03 µM and 28.63 ± 1.59 µM, respectively).


Subject(s)
Eugenia , Sesquiterpenes , Animals , Mice , Humans , Fruit , HEK293 Cells , Molecular Structure , RAW 264.7 Cells , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry
3.
J Med Chem ; 66(3): 1873-1891, 2023 02 09.
Article in English | MEDLINE | ID: mdl-36695404

ABSTRACT

AXL kinase is heavily involved in tumorigenesis, metastasis, and drug resistance of many cancers, and several AXL inhibitors are in clinical investigations. Recent studies demonstrated that the N-terminal distal region of AXL plays more important roles in cell invasiveness than its C-terminal kinase domain. Therefore, degradation of AXL may present a novel superior therapeutic approach than the kinase inhibitor therapy. Herein, we report the discovery of a series of new AXL PROTAC degraders. One representative compound 6n potently depletes AXL with a DC50 value of 5 nM in MDA-MB-231 TNBC cells. It also demonstrates significantly improved potencies against the AXL signaling activation, cell proliferation, migration and invasion of TNBC cells comparing with the corresponding kinase inhibitor. Moreover, the compound exhibits promising therapeutic potential both in patient-derived organoids and a xenograft mouse model of MDA-MB-231 cells.


Subject(s)
Receptor Protein-Tyrosine Kinases , Triple Negative Breast Neoplasms , Humans , Mice , Animals , Triple Negative Breast Neoplasms/pathology , Proto-Oncogene Proteins/metabolism , Cell Line, Tumor , Signal Transduction , Cell Proliferation , Disease Models, Animal
4.
Eur J Med Chem ; 244: 114862, 2022 Dec 15.
Article in English | MEDLINE | ID: mdl-36308779

ABSTRACT

REarranged during Transfection (RET) is a validated target for anticancer drug discovery and two selective RET inhibitors were approved by US FDA in 2020. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) becomes a major challenge for selective RET inhibitor therapies. Herein, we report a structure-based design of 1-methyl-3-((4-(quinolin-4-yloxy)phenyl)amino)-1H-pyrazole-4-carboxamide derivatives as new RET kinase inhibitors which are capable of suppressing the RETG810 C/R resistant mutants. One of the representative compounds, 8q, potently suppressed wild-type RET kinase with an IC50 value of 13.7 nM. It also strongly inhibited the proliferation of BaF3 cells stably expressing various oncogenic fusions of RET kinase with solvent-front mutations, e.g. CCDC6-RETG810C, CCDC6-RETG810R, KIF5B-RETG810C and KIF5B-RETG810R, with IC50 values of 15.4, 53.2, 54.2 and 120.0 nM, respectively. Furthermore, 8q dose-dependently inhibited the activation of RET and downstream signals and obviously triggered apoptosis in Ba/F3-CCDC6-RETG810 C/R cells. The compound also exhibited significant anti-tumor efficacy with a tumor growth inhibition (TGI) value of 66.9% at 30 mg/kg/day via i. p. in a Ba/F3-CCDC6-RETG810C xenograft mouse model. Compound 8q may be utilized as a lead compound for drug discovery combating acquired resistance against selective RET inhibitor therapies.


Subject(s)
Lung Neoplasms , Proto-Oncogene Proteins c-ret , Humans , Mice , Animals , Solvents , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Mutation , Transfection , Lung Neoplasms/drug therapy
5.
J Med Chem ; 65(4): 3249-3265, 2022 02 24.
Article in English | MEDLINE | ID: mdl-35119278

ABSTRACT

Aberrant FGF19/FGFR4 signaling is an oncogenic driver force for the development of human hepatocellular carcinoma (HCC). A series of 2-formyl tetrahydronaphthyridine urea derivatives were designed and synthesized as new covalently reversible inhibitors of FGFR4. The representative compound 9ka exhibited an IC50 value of 5.4 nM against FGFR4 and demonstrated extraordinary kinome selectivity. Compound 9ka also exhibited good oral pharmacokinetic properties with an AUC(0-t) value of 38 950.06 h·ng/mL, a T1/2 value of 3.06 h, and an oral bioavailability of 50.97%, at an oral dose of 25 mg/kg in Sprague-Dawley (SD) rats. Furthermore, compound 9ka induced significant tumor regressions in a xenograft mouse model of Hep3B2.1-7 HCC cell line without an obvious sign of toxicity upon 30 mg/kg oral administration. Compound 9ka may serve as a promising lead compound for further anticancer drug development.


Subject(s)
Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors , Urea/analogs & derivatives , Urea/pharmacology , Animals , Antineoplastic Agents/pharmacology , Area Under Curve , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Drug Design , Half-Life , Humans , Liver Neoplasms/drug therapy , Mice , Models, Molecular , Protein Kinase Inhibitors , Rats , Rats, Sprague-Dawley , Urea/pharmacokinetics , Xenograft Model Antitumor Assays
6.
ACS Med Chem Lett ; 12(4): 647-652, 2021 Apr 08.
Article in English | MEDLINE | ID: mdl-33859803

ABSTRACT

Covalent kinase inhibitors are rapidly emerging as a class of therapeutics with clinical benefits. Herein we report a series of selective 2-aminopyrimidine-based fibroblast growth factor receptor 4 (FGFR4) inhibitors exploring different types of cysteine-targeting warheads. The structure-activity relationship study revealed that the chemically tuned warheads α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine were suitable as covalent warheads for the design of selective FGFR4 inhibitors. Compounds 6a, 6h, and 6i selectively suppressed FGFR4 enzymatic activity with IC50 values of 53 ± 18, 45 ± 11, and 16 ± 4 nM, respectively, while sparing FGFR1/2/3. X-ray crystal structure and MALDI-TOF studies demonstrated that compound 6h bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound 6i with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. 6h and 6i might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.

7.
Nat Prod Bioprospect ; 11(1): 51-62, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32876846

ABSTRACT

Ten neolignans or norlignans (1-10) including eight new compounds were isolated from the whole bodies of Polyphaga plancyi Bolivar. Their structures were identified by spectroscopic data. Compounds 3, 4, 8, and 9 are racemates indicated by chiral HPLC analysis. Chiral separation followed by ECD calculations allowed to clarify the absolute configurations of all the antipodes. All the new compounds were evaluated for their biological properties toward extracellular matrix in rat renal proximal tubular cells, human cancer cells (K562, A549, and Huh7), EV71, ROCK2, JAK3, DDR1, and coagulation.

8.
Bioorg Chem ; 102: 104086, 2020 09.
Article in English | MEDLINE | ID: mdl-32688114

ABSTRACT

Pipajiains H-J (1-3), three new phenolic derivatives with an unusual sulfone group, pipajiamides A-C (4-6), three new amide derivatives, pipajiaine A (7), one new imidazole analogue, and pipajiaine B (8), a pair of new pyrrolidine derivatives, along with three known compounds were isolated from the insect Blaps japanensis. Their structures were identified by spectroscopic and computational methods. Chiral HPLC was used to separate the (-)- and (+)-antipodes of 4 and 8. Biological activities of all the new compounds against extracellular matrix in rat renal proximal tubular cells, human cancer cells (A549, Huh-7, and K562), COX-2, ROCK1, and JAK3 were evaluated. The results show that compounds 2, (+)-4, and (-)-4 are active against kidney fibrosis, whereas, compound 9 is active toward human cancer cells, inflammation, and JAK3 kinase.


Subject(s)
Coleoptera/chemistry , Nitrogen Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Sulfur/pharmacology , Animals , Cells, Cultured , Density Functional Theory , Dose-Response Relationship, Drug , Fibrosis/drug therapy , Humans , Janus Kinase 3/antagonists & inhibitors , Janus Kinase 3/metabolism , Molecular Structure , Nitrogen Compounds/chemistry , Nitrogen Compounds/isolation & purification , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/isolation & purification , Rats , Structure-Activity Relationship , Sulfur/chemistry , Sulfur/isolation & purification , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/metabolism
9.
Eur J Med Chem ; 203: 112552, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-32702585

ABSTRACT

Neurotrophic receptor tyrosine kinase (NTRK) fusions are oncogenic drivers for a variety of adult and pediatric tumors, validated by the US FDA approval of small molecular Trk inhibitors Larotrectinib (1, LOXO-101) and Entrectinib (2). However, gene mutation mediated resistance becomes a major challenge for Trk inhibitor therapies. Herein, we report the design, synthesis and Structure-Activity Relationship investigation of a series of 3-vinylindazole derivatives as new Trk inhibitors with low nanomolar potencies. A representative compound, 7mb, binds to TrkA/B/C with Kd values of 1.6, 3.1 and 4.9 nM, and suppresses their kinase functions with IC50 values of 1.6, 2.9 and 2.0 nM, respectively, but is obviously less potent for the majority of a panel of 403 wild-type kinases in a KINOMEscan selectivity investigation. The compound also potently suppresses proliferation of a panel of BaF3 cells stably transformed with NTRK fusions with IC50 values in low nM ranges. Additionally, the compound exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC50 values of 0.031 and 0.018 µM, respectively. Although the relatively poor oral bioavailability of 7mb will limit its further development, this compound may be utilized a lead molecule for further structural optimization.


Subject(s)
Drug Design , Indazoles/chemistry , Indazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor, trkA/antagonists & inhibitors , Tropomyosin/metabolism , Cell Line , Cell Proliferation/drug effects , Humans , Hydrogen Bonding , Indazoles/chemical synthesis , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 30(11): 127168, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32273216

ABSTRACT

Fourteen ansamycin derivatives including seven new herbimycins G-L (1-6) and divergolide O (7), and seven known analogues were isolated from a culture broth of the marine-derived Streptomyces sp. SCSGAA 0027. Their complete structures were determined by detailed analysis of spectroscopic data and quantum chemical calculations. Compounds 1-5 and 7 featured an additional eight-membered O-heterocycle that has rarely been reported for ansamycins, and the Z,Z- and E,E-configurations for Δ2,Δ4 were reported for the first time in geldanamycin analogues. Compound 1 exhibited weak inhibition activity towards Hsp90α with an IC50 value of 96 µM, 2-5 showed mild cytotoxicity against four human cancer cell lines with IC50 values ranging from 13 µM to 86 µM, and 7 had moderate anti-HSV-1 activity with an IC50 value of 19 µM and very weak cytotoxicity towards Vero cell. The possible biosynthetic pathways for 1-5 were proposed. And their structure-bioactivity relationship was also discussed.


Subject(s)
Antiviral Agents/chemistry , Rifabutin/analogs & derivatives , Streptomyces/chemistry , Antiviral Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/metabolism , Herpesvirus 1, Human/drug effects , Humans , Magnetic Resonance Spectroscopy , Molecular Conformation , Rifabutin/pharmacology , Staphylococcus aureus/drug effects , Stereoisomerism , Streptomyces/metabolism , Structure-Activity Relationship
11.
ACS Med Chem Lett ; 11(3): 379-384, 2020 Mar 12.
Article in English | MEDLINE | ID: mdl-32184973

ABSTRACT

DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3'-(imidazo[1,2-a]pyrazin-3-yl)-[1,1'-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound 8v potently inhibited DDR1 with an IC50 of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC50 = 1740 nM) and negligible activities against Bcr-Abl (IC50 > 10 µM) and c-Kit (IC50 > 10 µM). 8v also exhibited excellent selectivity in a KINOMEscan screening platform with 468 kinases. This compound dose-dependently suppressed NSCLC cell tumorigenicity, migration, and invasion. Collectively, these studies support its potential application for treatment of NSCLC.

12.
Nat Prod Res ; 34(16): 2269-2275, 2020 Aug.
Article in English | MEDLINE | ID: mdl-30518262

ABSTRACT

(+)- and (-)-gancochlearols A (1) and B (2), two pairs of dimeric mertoterpenoid enantiomers were isolated from the fruiting bodies of Ganoderma cochlear. Their structures were identified by spectroscopic methods. Biological assessments show that the enantiomers of 1 and 2 are cytotoxic against three human cancer cell lines (A549, K562, Huh-7) and could inhibit COX-2 expression with IC50 values less than 10 µM.


Subject(s)
Cyclooxygenase 2 Inhibitors/isolation & purification , Cytotoxins/isolation & purification , Ganoderma/chemistry , Terpenes/pharmacology , Antineoplastic Agents/analysis , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclooxygenase 2 Inhibitors/pharmacokinetics , Cytotoxins/pharmacology , Fruiting Bodies, Fungal/chemistry , Humans , Molecular Structure , Stereoisomerism , Terpenes/analysis , Terpenes/isolation & purification
13.
J Med Chem ; 63(5): 2114-2130, 2020 03 12.
Article in English | MEDLINE | ID: mdl-31244114

ABSTRACT

ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein (Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.


Subject(s)
Drug Design , MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Sulfonamides/pharmacology , Triazoles/pharmacology , Animals , Humans , Leucine Zippers/drug effects , MAP Kinase Kinase Kinases/chemistry , MAP Kinase Kinase Kinases/metabolism , Molecular Docking Simulation , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Structure-Activity Relationship , Sulfonamides/blood , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Triazoles/blood , Triazoles/chemical synthesis , Triazoles/chemistry , Benzenesulfonamides
14.
J Med Chem ; 62(16): 7431-7444, 2019 08 22.
Article in English | MEDLINE | ID: mdl-31310125

ABSTRACT

A series of 2-amino-2,3-dihydro-1H-indene-5-carboxamides were designed and synthesized as new selective discoidin domain receptor 1 (DDR1) inhibitors. One of the representative compounds, 7f, bound with DDR1 with a Kd value of 5.9 nM and suppressed the kinase activity with an half-maximal (50%) inhibitory concentration value of 14.9 nM. 7f potently inhibited collagen-induced DDR1 signaling and epithelial-mesenchymal transition, dose-dependently suppressed colony formation of pancreatic cancer cells, and exhibited promising in vivo therapeutic efficacy in orthotopic mouse models of pancreatic cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Discoidin Domain Receptor 1/antagonists & inhibitors , Neoplasms, Experimental/prevention & control , Pancreatic Neoplasms/prevention & control , Xenograft Model Antitumor Assays/methods , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Discoidin Domain Receptor 1/metabolism , Drug Design , Epithelial-Mesenchymal Transition/drug effects , Humans , Male , Mice, Inbred C57BL , Neoplasms, Experimental/metabolism , Pancreatic Neoplasms/metabolism , Rats, Sprague-Dawley , Tumor Stem Cell Assay
15.
Eur J Med Chem ; 166: 318-327, 2019 Mar 15.
Article in English | MEDLINE | ID: mdl-30731400

ABSTRACT

Axl is a new promising molecular target for antineoplastic therapies. A series of quinolone antibiotic derivatives were designed and synthesized as new selective Axl inhibitors. One of the most promising compound 8i bound tightly to Axl with a Kd value of 1.1 nM, and inhibited its kinase activity with an IC50 value of 26 nM. The compound also significantly inhibited the phosphorylation of Axl and dose dependently inhibited cell invasion and migration in TGF-ß1 induced MDA-MD-231 breast cancer cells. In addition, 8i demonstrated reasonable pharmacokinetic properties and exhibited extraordinary target selectivity over 468 kinases except for Flt3 (IC50 = 50 nM)), with a S(10) and S(35) value of 0.022 and 0.42 at 1.0 µM, respectively. Compound 8i may serve as a new valuable lead compound for future anticancer drug discovery.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Quinolones/chemistry , Quinolones/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Anti-Bacterial Agents/pharmacokinetics , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Male , Protein Kinase Inhibitors/pharmacokinetics , Quinolones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Axl Receptor Tyrosine Kinase
16.
J Asian Nat Prod Res ; 21(6): 542-550, 2019 Jun.
Article in English | MEDLINE | ID: mdl-29985069

ABSTRACT

Three pairs of meroterpenoids (±) cochlearoids N-P (1-3) were isolated from the fruiting bodies of Ganoderma cochlear. Their structures including absolute configurations were assigned by spectroscopic techniques. All the isolated compounds were tested for their inhibitory activities toward BRD4, human cancer cells, and micro-organisms. The results show that the enantiomers of (±)-1 are BRD4 inhibitors, (-)-1 and (+)-3 are cytotoxic against human cancer cells (K562) with IC50 values of 7.68 and 6.68 µM, respectively. Besides compounds (±)-2 and (±)-3 exhibit potent inhibitory activity against Staphylococcus aureus with IC50 values in the range of 5.43-17.99 µM.


Subject(s)
Ganoderma/chemistry , Phenols/chemistry , Terpenes/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Cell Line, Tumor , Fruiting Bodies, Fungal/chemistry , Humans , Microbial Sensitivity Tests , Molecular Structure , Nuclear Proteins/antagonists & inhibitors , Phenols/pharmacology , Terpenes/pharmacology , Transcription Factors/antagonists & inhibitors
17.
Fitoterapia ; 132: 82-87, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30521857

ABSTRACT

Two new nucleoside derivatives, named asponguanosines A and B (1 and 2), three new N-acetyldopamine analogues, aspongamides C-E (3-5), one new sesquiterpene, aspongnoid D (6), and three known compounds were isolated from the medicinal insect Aspongopus chinensis. Their structures including absolute configurations were assigned by using spectroscopic methods and ECD and 13C NMR calculations. Biological activities of compounds 3-7 towards human cancer cells, COX-2, ROCK1, and JAK3 were evaluated.


Subject(s)
Dopamine/analogs & derivatives , Heteroptera/chemistry , Nucleosides/chemistry , Animals , Carbon-Carbon Lyases/chemistry , Carbon-Carbon Lyases/isolation & purification , Cell Line, Tumor , China , Cyclooxygenase 2 , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/isolation & purification , Dopamine/chemistry , Dopamine/isolation & purification , Humans , Janus Kinase 3/antagonists & inhibitors , Molecular Structure , Nucleosides/isolation & purification , rho-Associated Kinases/antagonists & inhibitors
18.
Eur J Med Chem ; 157: 1361-1375, 2018 Sep 05.
Article in English | MEDLINE | ID: mdl-30196060

ABSTRACT

Aurora kinases play critical roles in the regulation of the cell cycle and mitotic spindle assembly. Aurora A kinase, a member of the Aurora protein family, is frequently highly expressed in tumors, and selective Aurora A inhibition serves as a significant component of anticancer therapy. However, designing highly selective Aurora A inhibitors is difficult because Aurora A and B share high homology and differ only by three residues in their ATP-binding pockets. Through structure-based drug design, we designed and synthesized a series of novel quinazolin-4-amine derivatives. These derivatives act as selective Aurora A kinase inhibitors by exploiting the structural differences between Aurora A and B. The selectivities of most compounds were improved (the best up to >757-fold) when comparing with the lead compound (3-fold). In vitro biochemical and cellular assays revealed that compound 6 potently inhibited Aurora A kinase and most human tumor cells. Furthermore, compound 6 effectively suppressed carcinoma, such as triple-negative breast cancers (TNBC) in an animal model. Therefore, compound 6 might serve as a promising anticancer drug. Moreover, through molecular dynamic (MD) analysis, we have identified that a salt bridge formed in Aurora B is key contributor for the isoform selectivity of the inhibitor. This salt bridge has not been previously detected in the reported crystal structure of Aurora B. These results might provide a crucial basis for the further development of highly potent inhibitors with high selectivity for Aurora A.


Subject(s)
Aurora Kinase A/antagonists & inhibitors , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Aurora Kinase A/metabolism , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity Relationship
19.
Fitoterapia ; 129: 167-172, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29969649

ABSTRACT

(+)- and (-)-Spirocochlealactones A-C (1-3), three pairs of new spiro meroterpenoidal dimeric enantiomers together with one known compound ganodilactone (4), were isolated from the fruiting bodies of Ganoderma cochlear. Their structures including absolute configurations were assigned by using spectroscopic methods and ECD calculations. All the isolated compounds were tested for their COX-2 inhibitory and cytotoxic activities toward human cancer lines (A549, K562, and Huh-7). The results show that all the compounds could inhibit COX-2 with IC50 values in the range of 1.29 to 3.63 µM. In addition, (+)-spirocochlealactone A and (+)-ganodilactone were found to be moderate activities against human cancer cell line A549 with the IC50 values of 7.14 and 9.47 µM, respectively.


Subject(s)
Cyclooxygenase 2 Inhibitors/pharmacology , Ganoderma/chemistry , Terpenes/pharmacology , A549 Cells , Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors/isolation & purification , Dogs , Fruiting Bodies, Fungal/chemistry , Humans , K562 Cells , Molecular Structure , Terpenes/isolation & purification
20.
J Med Chem ; 61(6): 2353-2371, 2018 03 22.
Article in English | MEDLINE | ID: mdl-29499108

ABSTRACT

Colony stimulating factor 1 receptor kinase (CSF1R) is a well validated molecular target for anticancer drug discovery. Herein, we report the design, synthesis, and structure-activity relationship study of 2-oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as new orally bioavailable CSF1R inhibitors. One of the most promising compounds, 3bw, potently inhibits CSF1R kinase with an IC50 value of 3.0 nM, while it is less potent against structurally related epidermal growth factor receptor (EGFR) and other kinases. The kinase inhibition of 3bw was further validated by Western blotting analysis in RAW264.7 macrophages. The molecule also potently blocks macrophage infiltration, abrogates the protumorigenic influences of macrophages, and exhibits reasonable pharmacokinetic profile. Compound 3bw may serve as a new valuable lead compound for future anticancer drug discovery.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Movement/drug effects , Drug Design , ErbB Receptors/chemistry , Macrophages/drug effects , Male , Mice , Models, Molecular , Molecular Structure , Neutrophil Infiltration/drug effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacokinetics , RAW 264.7 Cells , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
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