ABSTRACT
Microtubule affinity regulating kinase 4 (MARK4) becomes a unique anti-cancer drug target as its overexpression is responsible for different types of cancers. In quest of novel, effective MARK4 inhibitors, some acridone derivatives were synthesized, characterized and evaluated for inhibitory activity against human MARK4. Among all the synthesized compounds, three (7b, 7d and 7f) were found to have better binding affinity and enzyme inhibition activity in µM range as shown by fluorescence binding, ITC and kinase assays. Here we used functional assays of selected potential lead molecules with commercially available panel of 26 kinases of same family. A distinctive kinase selectivity profile was observed for each compound. The selective compounds were identified with submicromolar cellular activity against MARK4. Furthermore, in vitro antitumor evaluation against cancerous cells (MCF-7 and HepG2) revealed that compounds 7b, 7d and 7f inhibit cell proliferation and predominantly induce apoptosis in MCF-7 cells, with IC50 values of 5.2 ± 1.2 µM, 6.3 ± 1.2 µM, and 5.8 ± 1.4 µM respectively. In addition, these compounds significantly upsurge the oxidative stress in cancerous cells. Our observations support our approach for the synthesis of effective inhibitors against MARK4 that can be taken forward for the development of novel anticancer molecules targeting MARK4.
Subject(s)
Acridones/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Acridones/chemistry , Binding Sites , Cell Proliferation/drug effects , Cell Survival/drug effects , HEK293 Cells , Hep G2 Cells , Humans , MCF-7 Cells , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Protein Conformation , Protein Kinase Inhibitors/chemistryABSTRACT
Based on NCI8642, a series of gallocyanine derivatives was synthesized with modifications of the substituent groups in position 1, 2 and 4 of the phenoxazinone scaffold. The effectiveness of gallocyanines to inhibit DKK1/LRP6 interactions and Tau phosphorylation induced by prostaglandin J2 and DKK1 was elucidated by both experimental data and molecular docking simulations. Bis-alkylated with flexible alkyl ester groups on C1 and bis-benzyl gallocyanines provided the most active inhibitors, while amino derivatives on C2 of NCI8642 that have alkoxy or benzyloxy substituents on C4, were less active. Furthermore, it is shown that treating of SHSY5Y cells with NCI8642 derivatives activates Wnt signaling and increases the levels of pGSK3ß kinase and ß-catenin.
Subject(s)
Drug Design , Intercellular Signaling Peptides and Proteins/metabolism , Low Density Lipoprotein Receptor-Related Protein-6/metabolism , Oxazines/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Binding Sites , Cell Line, Tumor , Humans , Hydrogen Bonding , Intercellular Signaling Peptides and Proteins/chemistry , Low Density Lipoprotein Receptor-Related Protein-6/antagonists & inhibitors , Molecular Docking Simulation , Oxazines/pharmacology , Oxazines/therapeutic use , Phosphorylation/drug effects , Protein Interaction Domains and Motifs/drug effects , Structure-Activity Relationship , Wnt Signaling Pathway/drug effects , tau Proteins/metabolismABSTRACT
AIM: Alkylating agents and antimetabolites are cytotoxic drugs commonly used in cancer treatment. These medications are often associated with serious side effects on normal tissues and organs. METHODOLOGY: To improve the pharmacological profile of the alkylating agent POPAM and the antimetabolite 5-fluorouracil, novel integrin-targeted delivery systems based on c(RGDyK) were successfully synthesized. The new conjugates were tested in vitro against different cancer cells such as PC3, SKOV3, A549, MCF7 and MBA-MB-321. RESULTS & CONCLUSION: The c(RGDyK) conjugates of POPAM demonstrated better inhibitory effects and selectivity compared with c(RGDyK) and POPAM. The c(RGDyK) conjugates of 5-FUA demonstrated diverse inhibitory effects compared with c(RGDyK) and 5-FUA related to the levels of integrin expression, the conjugate stability and sensitivity of cancer cells to 5-FUA.
Subject(s)
Aniline Mustard/analogs & derivatives , Antineoplastic Agents/chemistry , Fluorouracil/chemistry , Integrins/metabolism , Peptides, Cyclic/chemistry , Propionates/chemistry , A549 Cells , Amino Acid Sequence , Aniline Mustard/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Fluorouracil/analysis , Fluorouracil/pharmacology , Humans , Integrins/antagonists & inhibitors , MCF-7 Cells , Magnetic Resonance Spectroscopy , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Oligopeptides/chemistryABSTRACT
Conjugates of cytotoxic agents with RGD peptides (Arg-Gly-Asp) addressed to ανß3, α5ß1 and ανß6 integrin receptors overexpressed by cancer cells, have recently gained attention as potential selective anticancer chemotherapeutics. In this review, the design and the development of RGD conjugates coupled to different small molecules including known cytotoxic drugs and natural products will be discussed.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Biological Products/chemistry , Drug Delivery Systems , Oligopeptides/metabolism , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemistry , Animals , Biological Products/administration & dosage , Cell Proliferation/drug effects , Humans , Integrins/metabolism , Molecular StructureABSTRACT
The first total synthesis of the antimicrobial natural product lynamicin D has been developed using a Suzuki coupling to construct the bisindole pyrrole skeleton. An evaluation of the biological activity of lynamicin D reveals that it has a minor effect on cell viability but it can modulate splicing of pre-mRNAs. We provide evidence that this effect is mainly due to the ability of lynamicin D to alter the levels of SRPK1, the key kinase involved in both constitutive and alternative splicing.
Subject(s)
Alternative Splicing , Indoles/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrroles/pharmacology , Animals , Cell Line, Tumor , Humans , Indoles/chemistry , Phosphorylation , Pyrroles/chemistry , Rats , Subcellular Fractions/enzymologyABSTRACT
Amino derivatives of NCI8642 were synthesized and evaluated as inhibitors of DKK1/LRP6 interactions. The new inhibitors were able to activate the Wnt signaling pathway as indicated by the increased levels of ß-catenin, and decrease the DKK1-induced Tau phosphorylation at serine 396.
Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Low Density Lipoprotein Receptor-Related Protein-6/metabolism , Oxazines/chemistry , Oxazines/pharmacology , Protein Interaction Maps/drug effects , HEK293 Cells , Humans , Models, Molecular , Oxazines/chemical synthesis , Phosphorylation/drug effects , Signal Transduction/drug effects , Structure-Activity Relationship , Wnt Proteins/metabolism , beta Catenin/metabolismABSTRACT
In search of safe and effective anti-Alzheimer disease agents a series of gallocyanine dyes have been synthesized and evaluated for their ability to inhibit LRPs/DKK1 interactions. Modulation of the interactions between LRPS and DKK1, regulate Wnt signaling pathway and affect Tau phosphorylation. The current efforts resulted in the identification of potent DKK1 inhibitors which are able to inhibit prostaglandin J2-induced tau phosphorylation at serine 396.