Discovery of a novel and highly selective JAK3 inhibitor as a potent hair growth promoter.

JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.

Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization.

Activation of Vγ9Vδ2 T cells with butyrophilin 3A1 (BTN3A1) agonists such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) has the potential to boost the immune response. Because HMBPP is highly charged and metabolically unstable, prodrugs may be needed to overcome these liabilities, but the prodrugs themselves may be limited by slow payload release or low plasma stability. To identify effective prodrug forms of a phosphonate agonist of BTN3A1, we have prepared a set of diesters bearing one aryl and one acyloxymethyl group. The compounds were evaluated for their ability to stimulate Vγ9Vδ2 T cell proliferation, increase production of interferon γ, resist plasma metabolism, and internalize into leukemia cells. These bioassays have revealed that varied aryl and acyloxymethyl groups can decouple plasma and cellular metabolism and have a significant impact on bioactivity (>200-fold range) and stability (>10 fold range), including some with subnanomolar potency. Our findings increase the understanding of the structure-activity relationships of mixed aryl/acyloxymethyl phosphonate prodrugs.

Small molecule '4ab' induced autophagy and endoplasmic reticulum stress-mediated death of aggressive cancer cells grown under adherent and floating conditions.

Metastasis is the leading cause of death in cancer patients and a major challenging aspect of cancer biology. Various adaptive molecular signaling pathways play a crucial role in cancer metastasis and later in the formation of secondary tumors. Aggressive cancer cells like triple negative breast cancer (TNBCs) are more inclined to undergo metastasis hence having a high recurrence rate and potential of micro-metastasis. Tumor cells in circulation known as circulating tumor cells (CTCs) offer an attractive drug target to treat metastatic disease. Cell cycle regulation and stress response of CTCs in blood has a crucial role in their survival and progression and thus may be considered therapeutically active hotspots. The cyclin D/cyclin-dependent kinase (CDK) pathway regulates cell cycle checkpoints, a process that is frequently dysregulated in cancer cells. Selective CDK inhibitors can limit the phosphorylation of cell cycle regulatory proteins by inducing cell cycle phase arrest, and thus may be an effective therapeutic strategy for aggressive cancer cells in their dividing phase at the primary or secondary site. However, during the floating condition, cancer cells halt their multiplication process and proceed through the various steps of metastasis. Current study showed that a novel CDK inhibitor 4ab induced autophagy and endoplasmic reticulum (ER) stress in agressive cancer cells grown under adherent and floating conditions resulting in paraptosis. Further, our results showed that 4ab efficiently induced cell death in aggressive cancer cells through ER stress-mediated activation of JNK signaling. Additionally, was observed that treatment of 4ab in tumor-bearing mice displayed a significant reduction in tumor burden and micro-metastasis. The outcome of these studies showed that 4ab can be a potential anti-tumor and anti-metastatic agent. Graphical representation of 4ab: image representing the effect of 4ab on death-inducing pathways in aggressive cancer cells. 4ab induces ER stress and activates autophagy leading to vacuolation of there by causing apoptosis in aggressive cancer cells.

Newly synthesized 3-sulfenylindole derivatives from 4-hydroxydithiocoumarin using an oxidative cross dehydrogenative coupling reaction (OCDCR): potential lead molecules for antiproliferative activity.

An expedient and efficient synthetic method was developed for the oxidative cross dehydrogenative coupling reaction between 4-hydroxydithiocoumarin and indole at the C-3 position regio-selectively using a combination of 10 mol% molecular iodine and TBHP in the presence of 10 mol% CuBr2 as an additive at room temperature. Mild reaction conditions, good yields and a broad substrate scope are some of the salient features of the present protocol. Additionally, the synthesized 3-sulfenylindoles derived from 4-hydroxydithiocoumarin were converted into biologically active sulfone derivatives. Interestingly, some of the compounds exhibit anti-cell proliferative activity on breast cancer (MCF-7) cells due to reactive oxygen species (ROS) mediated cell damage.

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model.

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.

Metal-free Cross-Dehydrogenative Coupling of HN-azoles with α-C(sp3)-H Amides via C-H Activation and Its Mechanistic and Application Studies.

A metal-free one step coupling reaction between various N-azole rings and diverse α-C(sp3)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1H-benzotriazoles, 1H-1,2,3-triazoles, 1H-1,2,4-triazoles, 1H-tetrazoles, 1H-pyrazoles, and 1H-benzimidazoles, and α-C(sp3)-H containing amides, such as N,N-dimethylacetamide, N,N-dimethylbenzamide, N-methylacetamide, N,N-diethylacetamide, N-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized N-azoles via direct covalent N-H bond transformations onto N-C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of α-C(sp3)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives.

I2/Aqueous TBHP-Catalyzed Coupling of Amides with Methylarenes/Aldehydes/Alcohols: Metal-Free Synthesis of Imides.

We present a metal-free method for the synthesis of imides by the direct coupling of NH-amides with methylarenes under iodine/aqueous TBHP conditions. The optimized conditions worked very well with benzaldehydes and benzyl alcohol and furnished the corresponding imides in good to excellent yields. A series of control and radical scavenger experiments were also performed, which suggested the involvement of radical pathways. The labeling experiment in the presence of (18)O-labeled H2O suggested water as a source of oxygen in the imides.

Metal free C-H functionalization of diazines and related heteroarenes with organoboron species and its application in the synthesis of a CDK inhibitor, meriolin 1.

Here, we report a metal-free cross-coupling reaction of diazines and related heteroarenes with organoboron species via C-H functionalization. The optimized conditions represent a metal-free method for the activation of aryl/heteroarylboronic acids, which undergo coupling with diazines and related heteroarenes. Optimized conditions also find application in the synthesis of a pyrimidine-based potent CDK inhibitor, meriolin1.

Cross-dehydrogenative coupling of azoles with α-C(sp3)-H of ethers and thioethers under metal-free conditions: functionalization of H-N azoles via C-H activation.

A metal-free cross-dehydrogenative coupling method for the synthesis of N-substituted azoles has been developed. The TBAI/TBHP system catalyzed the coupling of azoles with ethers and thioethers via α-C(sp(3))-H activation. Under the optimized conditions, a diverse range of un/substituted azoles such as 1H-benzimidazole, 9H-purine, 1H-benzotriazole, 1H-1,2,3-triazole, 1H-1,2,4-triazole, and 1H-pyrazole were successfully employed for coupling with various ethers and thioethers such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, diethyl ether, tetrahydrothiophene, and 1,3-dithiolane.

New method for C-H arylation/alkylation at α-position of cyclic aliphatic ethers by iron-oxide mediated reaction.

We report a new and efficient iron oxide catalyzed cross-coupling reaction between organometallic species such as alkyl/arylmagnesium halides or organolithium species and α-hydrogen bearing cyclic unbranched and branched aliphatic ethers via activation of C(sp(3))-H. In the presence of 1 mol% of iron oxide, five and six membered unbranched cyclic ethers such as tetrahydrofuran and tetrahydropyran gave good to excellent yields of cross-coupled products. Whereas, in case of branched ether such as 2-methyltetrahydrofuran, it was observed that the arylation occurred at both the sides and gave moderate yields of a mixture of regioisomers. Among the organometallic species used, alkyl organometallic reagents gave less yields as compared to aryl organometallics.

Iron oxide mediated direct C-H arylation/alkylation at α-position of cyclic aliphatic ethers.

We report a new and efficient iron oxide catalyzed cross-coupling reaction between organometallic species such as alkyl/arylmagnesium halides or organolithium species and α-hydrogen bearing cyclic aliphatic ethers via activation of C(sp(3))-H. This is the first example of iron oxide mediated direct C-C bond formation without expensive or toxic ligands.