Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma.

Background: Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor prognoses and therapy resistance. However, MYC itself has been one of the most challenging targets for cancer treatment. Here, we identify a novel marinopyrrole natural derivative, MP1, that shows desirable anti-MYC and anti-cancer activities in MB.

Analogs of Marinopyrrole A Show Enhancement to Observed Potency against Acute Toxoplasma gondii Infection.

The apicomplexan parasite Toxoplasma gondii is the causative agent of toxoplasmosis, a globally distributed infection with severe clinical consequences for immunocompromised individuals and developing fetuses. There are few available treatments, and these are associated with potentially severe adverse effects. Marinopyrrole A, a compound discovered in a marine species, has previously been found to exhibit potent antimicrobial activity, prompting our interest in exploring efficacy against Toxoplasma gondii.

Assessment of Tissue Distribution and Metabolism of MP1, a Novel Pyrrolomycin, in Mice Using a Validated LC-MS/MS Method.

MP1 is a novel marinopyrrole analogue with activity in MYCN amplified neuroblastoma cell lines. A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of MP1 in mouse plasma. Analyte separation was achieved using a Waters Acquity UPLCBEH C18 column (1.

Drugs for the Treatment of Zika Virus Infection.

Zika virus is an emerging flavivirus that causes the neurodevelopmental congenital Zika syndrome and that has been linked to the neuroinflammatory Guillain-Barré syndrome. The absence of a vaccine or a clinically approved drug to treat the disease combined with the likelihood that another outbreak will occur in the future defines an unmet medical need. Several promising drug candidate molecules have been reported via repurposing studies, high-throughput compound library screening, and de novo design in the short span of a few years.

Effects of novel pyrrolomycin MP1 in MYCN amplified chemoresistant neuroblastoma cell lines alone and combined with temsirolimus.

Background: The activity of MP1, a pyrrolomycin, was studied in MYCN amplified neuroblastoma (NB) alone and combined with temsirolimus (TEM).

Methods: Activity of MP1 was tested in MYCN amplified (BE-2c, IMR) and non amplified (SKN-AS) NB cells. The effect of MP1 on MYCN, MCL-1, cleaved PARP, LC3II/LC3I, bcl-2, BAX, and BRD-4 were determined by western blot and RNAseq.

Enamine Catalytic Annulation of Azonaphthalenes: An Access to Indole Derivatives.

The secondary-amine mediated [3 + 2] annulation of azonaphthalenes with aldehydes and ketones is described for the first time, which provides an alternative protocol for the synthesis of indole derivatives. It features a cheap and readily available catalyst, a broad scope of reactants, very mild reaction conditions, and high efficiency. Significantly different from the transition-metal-mediated processes, the enamine activation represents the first organic base-catalytic protocol for indole synthesis.

Remote Stereocontrolled Construction of Vicinal Axially Chiral Tetrasubstituted Allenes and Heteroatom-Functionalized Quaternary Carbon Stereocenters.

The direct diastereo- and enantioselective 1,8-conjugate additions of thiazolones and azlactones, respectively, to para-quinone methides generated in situ from propargylic alcohols have been achieved in the presence of chiral phosphoric acids. The remote stereocontrolled activation protocol provides an efficient and facile approach for the construction of vicinal axially chiral tetrasubstituted allenes and heteroatom-functionalized quaternary carbon stereocenters, which expands the synthetic potential of chiral phosphoric acids.

Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy.

Histone deacetylases (HDACs), encompassing at least 18 members, are promising targets for anticancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It has been well validated that an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and in potentiating synergistic effects.

Development and Validation of a Phenotypic High-Content Imaging Assay for Assessing the Antiviral Activity of Small-Molecule Inhibitors Targeting Zika Virus.

Zika virus (ZIKV) has been linked to the development of microcephaly in newborns, as well as Guillain-Barré syndrome. There are currently no drugs available to treat ZIKV infection, and accordingly, there is an unmet medical need for the discovery of new therapies. High-throughput drug screening efforts focusing on indirect readouts of cell viability are prone to a higher frequency of false positives in cases where the virus is viable in the cell but the cytopathic effect (CPE) is reduced or delayed.

Novel fluorinated pyrrolomycins as potent anti-staphylococcal biofilm agents: Design, synthesis, pharmacokinetics and antibacterial activities.

Staphylococcus aureus (SA) is a major cause of hospital- and community-associated bacterial infections in the U.S. and around the world.

Structure-Based Identification of Novel Ligands Targeting Multiple Sites within a Chemokine-G-Protein-Coupled-Receptor Interface.

CXCL12 is a human chemokine that recognizes the CXCR4 receptor and is involved in immune responses and metastatic cancer. Interactions between CXCL12 and CXCR4 are an important drug target but, like other elongated protein-protein interfaces, present challenges for small molecule ligand discovery due to the relatively shallow and featureless binding surfaces. Calculations using an NMR complex structure revealed a binding hot spot on CXCL12 that normally interacts with the I4/I6 residues from CXCR4.

Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential.

Rho kinases (ROCKs) belong to the serine-threonine family, the inhibition of which affects the function of many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two ROCK inhibitors have been approved for clinical use in Japan (fasudil and ripasudil) and one in China (fasudil).

Drug Design Targeting the CXCR4/CXCR7/CXCL12 Pathway.

Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal blood cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in various cancers, including lymphoma and leukemia, hepatocecullar, ovarian, colorectal, breast and lung cancer.

Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products.

Natural products provide a successful supply of new chemical entities (NCEs) for drug discovery to treat human diseases. Approximately half of the NCEs are based on natural products and their derivatives. Notably, marine natural products, a largely untapped resource, have contributed to drug discovery and development with eight drugs or cosmeceuticals approved by the U.

Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors.

Inhibition of anti-apoptotic Mcl-1 is a promising anticancer strategy to overcome the survival and chemoresistance of a broad spectrum of human cancers. We previously reported on the identification of a natural product marinopyrrole A (1) that induces apoptosis in Mcl-1-dependent cells through Mcl-1 degradation. Here, we report the design and synthesis of novel marinopyrrole-based analogs and their evaluation as selective inhibitors of Mcl-1 as well as dual Mcl-1/Bcl-xL inhibitors.

Structural analysis of a novel small molecule ligand bound to the CXCL12 chemokine.

CXCL12 binds to CXCR4, promoting both chemotaxis of lymphocytes and metastasis of cancer cells. We previously identified small molecule ligands that bind CXCL12 and block CXCR4-mediated chemotaxis. We now report a 1.

Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein Bim.

A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1.

Marinopyrrole derivatives as potential antibiotic agents against methicillin-resistant Staphylococcus aureus (III).

The marine natural product, marinopyrrole A (1), was previously shown to have significant antibiotic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Although compound (1) exhibits a significant reduction in MRSA activity in the presence of human serum, we have identified key modifications that partially restore activity. We previously reported our discovery of a chloro-derivative of marinopyrrole A (1a) featuring a 2-4 fold improved minimum inhibitory concentration (MIC) against MRSA, significantly less susceptibility to serum inhibition and rapid and concentration-dependent killing of MRSA.

Cyclic marinopyrrole derivatives as disruptors of Mcl-1 and Bcl-x(L) binding to Bim.

A series of novel cyclic marinopyrroles were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-x(L), was evaluated using ELISA assays. Both atropisomers of marinopyrrole A (1) show similar potency.

Marinopyrrole derivatives as potential antibiotic agents against methicillin-resistant Staphylococcus aureus (II).

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem, causing severe and intractable infections worldwide. MRSA is resistant to all beta-lactam antibiotics, and alternative treatments are limited. A very limited number of new antibiotics have been discovered over the last half-century, novel agents for the treatment of MRSA infections are urgently needed.

Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction.

The chemokine CXCL12 and its G protein-coupled receptor (GPCR) CXCR4 are high-priority clinical targets because of their involvement in metastatic cancers (also implicated in autoimmune disease and cardiovascular disease). Because chemokines interact with two distinct sites to bind and activate their receptors, both the GPCRs and chemokines are potential targets for small molecule inhibition. A number of chemokines have been validated as targets for drug development, but virtually all drug discovery efforts focus on the GPCRs.

Marinopyrrole derivatives as potential antibiotic agents against methicillin-resistant Staphylococcus aureus (I).

Infections caused by drug-resistant pathogens are on the rise. The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains exemplifies the urgent need for new antibiotics. The marine natural product, marinopyrrole A, was previously shown to have potent antibiotic activity against Gram-positive pathogens, including MRSA.

Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation.

The anti-apoptotic Bcl-2 family of proteins, including Bcl-2, Bcl-X(L) and Mcl-1, are well-validated drug targets for cancer treatment. Several small molecules have been designed to interfere with Bcl-2 and its fellow pro-survival family members. While ABT-737 and its orally active analog ABT-263 are the most potent and specific inhibitors to date that bind Bcl-2 and Bcl-X(L) with high affinity but have a much lower affinity for Mcl-1, they are not very effective as single agents in certain cancer types because of elevated levels of Mcl-1.

Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors.

Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC(50) = 650 nM) and ROCK2 (IC(50) = 670 nM), whereas compound 24 was more selective for ROCK2 (IC(50) = 100 nM) over ROCK1 (IC(50) = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site.