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1.
J Med Chem ; 2024 May 16.
Article in English | MEDLINE | ID: mdl-38754045

ABSTRACT

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system and the unmet need for MS treatment demands new therapeutic development. Particularly, PI3Kδ is a high-value target for autoimmune disease, while the investigation of PI3Kδ inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3Kδ inhibitors for MS treatment. Compound 31, designed via nitrogen bioisosterism, displayed excellent PI3Kδ inhibitory activity and selectivity. In vitro assay showed that 31 exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4+, CD8+, and CD3+ T cells. In the experimental autoimmune encephalomyelitis (EAE) model, 31 showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound 31 could significantly inhibit the PI3K/AKT/mTOR signaling pathway and inhibited T-cell proliferation and differentiation. Overall, this work provides a new structural PI3Kδ inhibitor and a new vision for MS therapy.

2.
Chem Sci ; 15(14): 5211-5217, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38577354

ABSTRACT

Indoles are privileged chemical entities in natural products and drug discovery. Indole-fused heterocycles, particularly seven-membered ones, have received increasing attention due to their distinctive chemical characteristics and wide spectrum of bioactivities. However, the synthetic access to these compounds is highly limited. Herein, we report a unique multicomponent reaction (MCR) for modular assembly of indole-fused seven-membered heterocycles. In this process, indole, formaldehyde and amino hydrochloride could assemble rapidly to yield indole-fused oxadiazepines, and another addition of sodium thiosulphate would furnish indole-fused thiadiazepines. The biological evaluation disclosed the promising anticancer activity of these compounds. Furthermore, this MCR could be applicable in the late-stage and selective modifications of peptides. Therefore, this work provides a powerful strategy for indole functionalization and valuable tool for construction of seven-membered heterocycles.

3.
J Med Chem ; 67(8): 6638-6657, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38577724

ABSTRACT

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-d]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that (S)-36 exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability (F = 59.6%). In the MOLM-13 subcutaneous xenograft model, (S)-36 could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, (S)-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo. Thus, compound (S)-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Class I Phosphatidylinositol 3-Kinases , Leukemia, Myeloid, Acute , Phosphoinositide-3 Kinase Inhibitors , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Animals , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors/chemistry , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacokinetics , Cell Proliferation/drug effects , Mice , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/metabolism , Structure-Activity Relationship , Apoptosis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Xenograft Model Antitumor Assays , Drug Discovery , Mice, Nude , Molecular Docking Simulation , Male
4.
Life Sci ; 347: 122662, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38670450

ABSTRACT

AIMS: PI3Kδ is expressed predominately in leukocytes and is commonly found to be aberrantly activated in human B-cell lymphomas. Although PI3Kδ has been intensively targeted for discovering anti-lymphoma drugs, the application of currently approved PI3Kδ inhibitors has been limited due to unwanted systemic toxicities, thus warranting the development of novel PI3Kδ inhibitors with new scaffolds. MAIN METHODS: We designed TYM-3-98, an indazole derivative, and evaluated its selectivity for all four PI3K isoforms, as well as its efficacy against various B-cell lymphomas both in vitro and in vivo. KEY FINDINGS: We identified TYM-3-98 as a highly selective PI3Kδ inhibitor over other PI3K isoforms at both molecular and cellular levels. It showed superior antiproliferative activity in several B-lymphoma cell lines compared with the approved first-generation PI3Kδ inhibitor idelalisib. TYM-3-98 demonstrated a concentration-dependent PI3K/AKT/mTOR signaling blockage followed by apoptosis induction. In vivo, TYM-3-98 showed good pharmaceutical properties and remarkably reduced tumor growth in a human lymphoma xenograft model and a mouse lymphoma model. SIGNIFICANCE: Our findings establish TYM-3-98 as a promising PI3Kδ inhibitor for the treatment of B-cell lymphoma.


Subject(s)
Antineoplastic Agents , Class I Phosphatidylinositol 3-Kinases , Lymphoma, B-Cell , Phosphoinositide-3 Kinase Inhibitors , Xenograft Model Antitumor Assays , Humans , Animals , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/pathology , Mice , Antineoplastic Agents/pharmacology , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Indazoles/pharmacology , Indazoles/therapeutic use , Apoptosis/drug effects , Cell Proliferation/drug effects , Female , Signal Transduction/drug effects , Mice, Nude
5.
Acta Pharmacol Sin ; 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38514863

ABSTRACT

Status epilepticus (SE), a serious and often life-threatening medical emergency, is characterized by abnormally prolonged seizures. It is not effectively managed by present first-line anti-seizure medications and could readily develop into drug resistance without timely treatment. In this study, we highlight the therapeutic potential of CZL80, a small molecule that inhibits caspase-1, in SE termination and its related mechanisms. We found that delayed treatment of diazepam (0.5 h) easily induces resistance in kainic acid (KA)-induced SE. CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic time window to 3 h following SE, and also protected against neuronal damage. Interestingly, the effect of CZL80 on SE termination was model-dependent, as evidenced by ineffectiveness in the pilocarpine-induced SE. Further, we found that CZL80 did not terminate KA-induced SE in Caspase-1-/- mice but partially terminated SE in IL1R1-/- mice, suggesting the SE termination effect of CZL80 was dependent on the caspase-1, but not entirely through the downstream IL-1ß pathway. Furthermore, in vivo calcium fiber photometry revealed that CZL80 completely reversed the neuroinflammation-augmented glutamatergic transmission in SE. Together, our results demonstrate that caspase-1 inhibitor CZL80 terminates diazepam-resistant SE by blocking glutamatergic transmission. This may be of great therapeutic significance for the clinical treatment of refractory SE.

6.
Curr Med Chem ; 31(15): 2021-2051, 2024.
Article in English | MEDLINE | ID: mdl-38310392

ABSTRACT

Inflammasomes are multimeric protein complexes that can detect various physiological stimuli and danger signals. As a result, they perform a crucial function in the innate immune response. The NLRP3 inflammasome, as a vital constituent of the inflammasome family, is significant in defending against pathogen invasion and preserving cellhomeostasis. NLRP3 inflammasome dysregulation is connected to various pathological conditions, including inflammatory diseases, cancer, and cardiovascular and neurodegenerative diseases. This profile makes NLRP3 an applicable target for treating related diseases, and therefore, there are rising NLRP3 inhibitors disclosed for therapy. Herein, we summarized the updated advances in the structure, function, and inhibitors of NLRP3 inflammasome. Moreover, we aimed to provide an overview of the existing products and future directions for drug research and development.


Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Immunity, Innate
7.
Adv Sci (Weinh) ; 11(7): e2305432, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38126681

ABSTRACT

Acute lung injury (ALI) is one of the most common complications in COVID-19 and also a syndrome of acute respiratory failure with high mortality rates, but lacks effective therapeutic drugs. Natural products provide inspiration and have proven to be the most valuable source for bioactive molecule discovery. In this study, the chemical evolution of the natural product Tanshinone IIA (Tan-IIA) to achieve a piperidine-fused scaffold through a synthetic route of pre-activation, multi-component reaction, and post-modification is presented. Through biological evaluation, it is pinpointed that compound 8b is a standout candidate with remarkable anti-inflammation and anti-oxidative stress properties, coupled with low toxicity. The mechanistic study unveils a multifaceted biological profile of 8b and shows that 8b is highly efficient in vivo for the treatment of ALI. Therefore, this work not only provides an effective strategy for the treatment of ALI, but also offers a distinctive natural product-inspired drug discovery.


Subject(s)
Acute Lung Injury , Respiratory Distress Syndrome , Humans , Evolution, Chemical , Acute Lung Injury/drug therapy , Oxidative Stress
8.
J Med Chem ; 66(17): 11905-11926, 2023 09 14.
Article in English | MEDLINE | ID: mdl-37606563

ABSTRACT

PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amine-tethered 3-methyl-1-aryl-1H-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages. (S)-29 was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivo administration of (S)-29 at 10 mg/kg dosage could significantly ameliorate histopathological changes and attenuate lung inflammation in lung tissues of LPS-challenged mice. Molecular docking demonstrated the success of scaffold hopping design. Overall, (S)-29 is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.


Subject(s)
Acute Lung Injury , Animals , Mice , Molecular Docking Simulation , Acute Lung Injury/drug therapy , Amines , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Biological Availability
9.
Nat Commun ; 14(1): 4806, 2023 Aug 09.
Article in English | MEDLINE | ID: mdl-37558669

ABSTRACT

Indole alkaloids are one of the largest alkaloid classes, proving valuable structural moiety in pharmaceuticals. Although methods for the synthesis of indole alkaloids are constantly explored, the direct single-step synthesis of these chemical entities with broad structural diversity remains a formidable challenge. Herein, we report a modular assembly of tetrahydrocarboline type of indole alkaloids from simple building blocks in a single step while showing broad compatibility with medicinally relevant functionality. In this protocol, the 2-alkylated or 3-alkylated indoles, formaldehyde, and amine hydrochlorides could undergo a one-pot reaction to deliver γ-tetrahydrocarbolines or ß-tetrahydrocarbolines directly. A wide scope of these readily available starting materials is applicable in this process, and numerous structural divergent tetrahydrocarbolines could be achieved rapidly. The control reaction and deuterium-labelling reaction are conducted to probe the mechanism. And mechanistically, this multicomponent reaction relies on a multiple alkylamination cascade wherein an unusual C(sp3)-C(sp3) connection was involved in this process. This method could render rapid access to pharmaceutically interesting compounds, greatly enlarge the indole alkaloid library and accelerate the lead compound optimization thus facilitating drug discovery.

10.
J Org Chem ; 88(16): 12150-12161, 2023 Aug 18.
Article in English | MEDLINE | ID: mdl-37498054

ABSTRACT

A multicomponent reaction of N-indole carboxylic acids, aldehydes, amines, and C2 building blocks can be transformed to structurally diverse ß-indole carboxamide amino amides. In this multicomponent reaction, the ynamides and triazenyl alkynes act as the C2 building block, and this protocol features readily available starting materials, high atom economy, and mild reaction conditions. Besides, the acyl triazene group in the product can be easily transformed to differential groups to expand the structural diversity.

11.
J Med Chem ; 66(15): 10791-10807, 2023 08 10.
Article in English | MEDLINE | ID: mdl-37498552

ABSTRACT

The development of histone deacetylase (HDAC) inhibitors for treating hematologic malignancies has been widely investigated, while their role in hepatocellular carcinoma (HCC) remains unexplored. In this study, we employed a scaffold-hopping design and a multicomponent synthesis approach to develop a novel series of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridines as HDAC inhibitors. There were a total of 29 compounds achieved with flexible linkers and zinc-binding groups, wherein compound 12k was identified as a promising candidate with good HDAC inhibitory activity, pharmacokinetic profiles, and potency. It exhibited significant therapeutic efficacy in HCC cell lines (IC50 = 30 nM for Bel-7402) and xenograft models (76% inhibition for Bel-7402 xenografts, P.O. at 20 mg/kg, QOD, for 14 days) and was found to upregulate the acetylation of histone H3 and α-tubulin, leading to apoptosis and autophagy in HCC models. Molecular docking studies indicated a unique T-shaped conformation of 12k with the catalytic domain of HDAC1. Therefore, this work provides a new structure design for HDAC inhibitors and also offers a promising treatment for HCC.


Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/chemistry , Liver Neoplasms/pathology , Molecular Docking Simulation , Apoptosis , Pyridines/pharmacology , Pyridines/therapeutic use , Cell Line, Tumor , Cell Proliferation , Histone Deacetylase 1/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use
12.
Nat Chem ; 15(5): 597-598, 2023 May.
Article in English | MEDLINE | ID: mdl-37055573
13.
J Med Chem ; 66(4): 2211-2234, 2023 02 23.
Article in English | MEDLINE | ID: mdl-36739538

ABSTRACT

Clinically, antibiotics are widely used to treat infectious diseases; however, excessive drug abuse and overuse exacerbate the prevalence of drug-resistant bacterial pathogens, making the development of novel antibiotics extremely difficult. Antimicrobial peptide (AMP) is one of the most promising candidates for overcoming bacterial resistance owing to its unique structure and mechanism of action. This study examines the development of small molecular mimetics of AMPs over the past two decades. These mimetics can selectively disrupt membranes, which are the characteristic antibacterial mechanism of AMPs. In addition, the advantages and disadvantages of small AMP mimetics are discussed. The small molecular mimetics of AMPs are anticipated to garner interest and investment in discovering new antibiotics. This Perspective will assist in revitalizing the golden age of antibiotics in the current era of combating bacterial resistance.


Subject(s)
Bacterial Infections , Communicable Diseases , Humans , Antimicrobial Cationic Peptides/pharmacology , Anti-Bacterial Agents/pharmacology , Bacterial Infections/drug therapy , Bacteria
14.
J Med Chem ; 66(4): 2946-2963, 2023 02 23.
Article in English | MEDLINE | ID: mdl-36786612

ABSTRACT

Natural products provide inspiration and have proven to be the most valuable source for drug discovery. Herein, we report a scaffold hybrid strategy of Tanshinone I for the discovery of NLRP3 inflammasome inhibitors. 36 compounds were designed and synthesized, and the cheminformatic analyses showed that these compounds occupy a unique chemical space. The biological evaluation identified compounds 5j, 12a, and 12d as NLRP3 inflammasome inhibitors with significant potency, selectivity, and drug-likeness. Mechanistic studies revealed that these Tanshinone I derivatives could inhibit the degradation of the protein NLRP3 and block the oligomerization of NLRP3-induced apoptosis-associated speck-like proteins, thus inhibiting NLRP3 inflammasome activation. In addition, the water solubility, in vitro metabolic stability, and oral bioavailability of these compounds were also greatly improved compared to Tanshinone I. Therefore, this protocol provides a new structural evolution of Tanshinone I and a new class of potent NLRP3 inflammasome inhibitors.


Subject(s)
Biological Products , Inflammasomes , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein , Piperidines
15.
Org Lett ; 25(2): 443-448, 2023 Jan 20.
Article in English | MEDLINE | ID: mdl-36627257

ABSTRACT

A modular and practical click chemistry for atroposelective synthesis of 1-triazolyl-2-naphthylamines is developed. In this protocol, a variety of aromatic or aliphatic azides, and 1-alkynyl-2-naphthylamines could be assembled into valuable 1-triazlyl-2-naphthylamine scaffolds via a [3 + 2] cycloaddition under Rh-catalysis. This asymmetric click technology features easily accessible starting materials, mild reaction conditions, facile scalability, and good enantioselectivity. The good thermostability of products showcases great applicable potential, and the synthetic transformations further expand the molecular diversity of atropisomers.

16.
J Med Chem ; 65(23): 15710-15724, 2022 12 08.
Article in English | MEDLINE | ID: mdl-36399795

ABSTRACT

Selective glucocorticoid receptor modulators (SGRMs), which can dissociate the transactivation from the transrepression of the glucocorticoid receptor (GR), are regarded as very promising therapeutics for inflammatory and autoimmune diseases. We previously discovered a SGRM HP-19 based on the passive antagonistic conformation of GR and bioassays. In this study, we further analyzed the dynamic changes of the passive antagonistic state upon the binding of HP-19 and designed and synthesized 62 N-acyl-6-sulfonamide-tetrahydroquinoline derivatives by structural optimization of HP-19. Therein, compound B53 exhibits the best transrepression activity (IC50 NF-κB = 0.009 ± 0.001 µM) comparable with dexamethasone (IC50 NF-κB = 0.005 ± 0.001 µM) and no transactivation activity. B53 can efficiently reduce the expression of inflammatory factors IL-6, IL-1ß, TNF-α, and so on and makes a milder adverse effect and is highly specific to GR. Furthermore, B53 is able to significantly relieve dermatitis on a mouse model via oral drug intervention.


Subject(s)
Glucocorticoids , Receptors, Glucocorticoid , Animals , Mice , NF-kappa B , Sulfonamides/pharmacology
17.
J Med Chem ; 65(19): 13074-13093, 2022 10 13.
Article in English | MEDLINE | ID: mdl-36154033

ABSTRACT

The androgen receptor (AR) antagonists are efficient therapeutics for the treatment of prostate cancer (PCa). All the approved AR antagonists to date are targeted to the ligand-binding pocket (LBP) of AR and have suffered from various drug resistances, whereas AR antagonist targeting non-LBP site of AR is conceived as a promising strategy. Through the scaffold hopping of AR LBP antagonists, the 2-chloro-4-(1H-pyrazol-1-yl)benzonitrile was designed as a new core structure for AR antagonists. A total of 46 compounds were synthesized and biologically evaluated to disclose compounds 2f, 2k, and 4c, exhibiting potent AR antagonistic activities (IC50 up to 69 nM), force against antiandrogen resistance, and untraditional targeting site of probably AR binding function 3. Therein, 4c exhibited effective tumor growth inhibition in LNCaP xenograft study upon oral administration. This work provides a novel chemical scaffold for AR antagonists and offers new perspective for the development of PCa therapy.


Subject(s)
Prostatic Neoplasms , Receptors, Androgen , Acetamides/pharmacology , Androgen Antagonists/pharmacology , Androgen Receptor Antagonists/chemistry , Cell Line, Tumor , Cell Proliferation , Humans , Ligands , Male , Prostatic Neoplasms/pathology , Pyrazoles , Receptors, Androgen/metabolism
18.
Bioorg Med Chem Lett ; 75: 128946, 2022 11 01.
Article in English | MEDLINE | ID: mdl-35985458

ABSTRACT

The voltage-gated sodium (Nav) channel is one of most important targets for treatment of epilepsy, and rufinamide is an approved third-generation anti-seizure drug as Nav1.1 channel blocker. Herein, by triazenylation of rufinamide, we reported the triazenyl triazoles as new Nav1.1 channel blocker for treatment of epilepsy. Through the electrophysiological activity assay, compound 6a and 6e were found to modulate the inactivation voltage of Nav 1.1 channel with shift of -10.07 mv and -11.28 mV, respectively. In the pentylenetetrazole (PTZ) mouse model, 6a and 6e reduced the seizure level, prolonged seizure latency and improved the survival rate of epileptic mice at an intragastric administration of 50 mg/kg dosage. In addition, 6a also exhibited promising effectiveness in the maximal electroshock (MES) mouse model and possessed moderate pharmacokinetic profiles. These results demonstrated that 6a was a novel Nav1.1 channel blocker for treatment of epilepsy.


Subject(s)
Epilepsy , Pentylenetetrazole , Animals , Disease Models, Animal , Epilepsy/drug therapy , Mice , Sodium , Sodium Channel Blockers/pharmacology , Sodium Channel Blockers/therapeutic use , Triazoles/pharmacology , Triazoles/therapeutic use , Voltage-Gated Sodium Channel Blockers/pharmacology , Voltage-Gated Sodium Channel Blockers/therapeutic use
19.
Angew Chem Int Ed Engl ; 61(28): e202205037, 2022 07 11.
Article in English | MEDLINE | ID: mdl-35508703

ABSTRACT

The cycloaddition of azides and alkynes is the leading click chemistry technology and has been widely used in drug discovery, biology and material sciences. However, the development of a modular and scalable enantioselective click cycloaddition remains a long-standing challenge. Herein, we report a rhodium-catalyzed enantioselective click cycloaddition of azides and alkynes for rapid and modular access to atropisomeric triazoles in excellent yields and enantioselectivities. The process is mild, efficient and scalable, and features broad substrate scope.


Subject(s)
Azides , Rhodium , Alkynes , Catalysis , Click Chemistry , Copper , Cycloaddition Reaction
20.
Bioorg Med Chem Lett ; 69: 128798, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35580725

ABSTRACT

The success of stem cells therapy to treat neurodegenerative diseases is currently restricted by the lack of suitable stem cells. Mesenchymal stem cells (MSCs) have demonstrated several advantages as seed-cells for the stem cells therapy. In particular, the low immunogenicity and multiple lineages differentiation capability enables the possibility of using MSCs to treat neurodegenerative diseases. However, a more potent neuronal differentiation capacity of MSCs is required during a success treatment against neurodegenerative diseases. Bioengineering using small molecules to boost the neuronal differentiation of MSCs has been proposed as a promising strategy. Herein, we developed a new series of (2-phenylthiazol-4-yl)urea derivatives and one of them, 18g were observed to successfully promote neuronal differentiation of MSCs after culturing MSCs with 18g for 4 days. In addition, neither significant cytotoxicity nor cell cycle altering were found after the incubation. Interestingly, the osteogenic differentiation potential of MSCs was not affected after 18g treatment. The present study provides a promising small molecule to boost the innate neuronal differentiation capacity of MSCs with no serious detrimental effects.


Subject(s)
Mesenchymal Stem Cells , Neurodegenerative Diseases , Cell Differentiation , Cells, Cultured , Humans , Neurodegenerative Diseases/metabolism , Osteogenesis , Urea/metabolism , Urea/pharmacology
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