Matrix metalloproteinases
A. R. Genazzani in Hormone Replacement Therapy and Cancer, 2020
Currendy, a number of MMP inhibitors have been developed and some are in clinical trials as anti-metastatic or anti-cancer therapies. Although many of the initial trials were quite promising, some complications have become apparent in the human trials, with the most severe side-effect being tendonitis in the joints of the shoulders, hands and knees39,40. These results indicate the necessity for further investigation into the normal biological functions of MMPs. Marimastat®, a potent broadspectrum inhibitor of MMPs, proved to be effective in phase I and II trials against colon, ovarian, prostate, lung and pancreatic cancers. Recently, phase III clinical trials involving Marimastat were halted as it was found to be performing worse than the placebo. The bryostatins are a group of naturally occurring macrocyclic lactones which inhibit MMP activity through down-regulation of the protein kinase C pathway. Recently, a number of investigators have begun testing bryostatin compounds for their effectiveness as tumoristatic agents. AG3340/prinostatin has been shown to inhibit the proliferation and invasion of glioma cells in vitro41. In early 2001, phase III clinical trials which were examining the effects of prinostatin on prostate and lung cancers were halted. Phase II trials involving patients with earlier stages of the disease, however, are set to continue.
Diversity Analysis of Indian Mangrove Organisms to Explore Their Potential in Novel and Value-Added Biomolecules
Jayanta Kumar Patra, Gitishree Das, Sanjeet Kumar, Hrudayanath Thatoi in Ethnopharmacology and Biodiversity of Medicinal Plants, 2019
Mangrove organisms such as sponge have many useful compounds such as cytarabine (Ara C), Vidarabine (Ara-A), Eribulin Mesylate (E7389) which are all FDA approved and targets dangerous diseases such as cancer (Mayer et al., 2016; Newman and Cragg, 2016) (Table 2.3). Other mangrove organisms such as Tunicate, Mollusca, Nudibranch also targets the disease, cancer. The omega 3 fatty acid ethyl esters from fish can be used for the treatment of Hypertriglyceridemia. Some important compounds such as Brentuximab Vedotin (SGN-35) Elisidesin, Glembatumumab Vedotin (CDX 011), SGN-75, ASG-5ME can be obtained from Mollusca majorly found in Baratang and Krishna Godavari mangroves. The bacterium Bryozoa gives Bryostatin, which can treat cancer and Alzheimer’s disease. The soft Coral produces pseudopterosins whose molecular target is Eicosanoid Metabolism and helps in wound healing. The compound Trabectedin (ET 743), which belongs to the alkaloid class targets the minor, grooves of DNA and helps in the treatment of cancer. The compound, Eribulin Mesylate (E7389) obtained from the sponge targets the microtubules for the treatment of cancer. Zincoside, obtained from cone nail is used as an analgesic drug. The compound DMXBA (GTS-21) obtained from worm targets the alpha-7 Nicotinic Acetylcholine Receptor and helps in the treatment of cognition schizophrenia (Table 2.3). Mangrove pharmaceuticals can be used as cytostatic drugs, antiviral drugs, analgetic drugs, antihyperlipidemic drugs and can also be used as diagnostic and experimental tools. The cosmetics industry is also stepping towards the sea, so as to find new ingredients (Fenical et al., 2009; Martins et al., 2014).
Marine Natural Products and Chemistry
Se-Kwon Kim in Marine Biochemistry, 2023
Bryostatin is a polyketide isolated from the bryozoan Buguna neritina, which is effective in both anticancer and immune-modulating activity (Suffness et al., 1989). Its mechanism of action is via the activation of protein kinase C-mediated cell-signal transduction pathways. The drug is under the clinical trial of phase II for chronic lymphocytic leukemia. Non-Hodgkin’s lymphoma and multiple myeloma via a cooperative research and development agreement between the National Cancer Institute (NCI) and Bristol Myers Squibb. Ecteinascidin-743, an alkaloid isolated from the ascidian Ecteinascidia turbinate, is under the phase I clinical trial for ovarian cancer. Discodermolide, a polyketide isolated from marine sponges of the class Discodermia, acts as an immunosuppressive and anticancer agent that inhibits cell proliferation by intrusion of the cells’ microtubule network (Hart, 1997). It is also effective against breast cancer and has been licensed by the Harbor Branch Oceanographic Institution and Novartis Pharmaceutical Corporation. Another promising compound from the marine sponge is halichondrin B, isolated from marine sponge from New Zealand, Lissodendoryx sp. Apart from the previously mentioned drugs, many secondary metabolites, such as alkaloids, terpenoids, polyketides, peptides, steroids, sugars, and shikimic acid derivatives, were isolated from marine sponges and still research goes on in order to identify their biological activities, including anti-microbial, anti-tumor, anti-diabetic, anti-inflammatory, anti-malarial, anti-fouling, and anti-protozoal, with higher industrial and therapeutic potential (Mayer et al., 2017; Agrawal et al., 2018).
SARS, MERS and SARS-CoV-2 (COVID-19) treatment: a patent review
Published in Expert Opinion on Therapeutic Patents, 2020
José Adão Carvalho Nascimento Junior, Anamaria Mendonça Santos, Lucindo José Quintans-Júnior, Cristiani Isabel Banderó Walker, Lysandro Pinto Borges, Mairim Russo Serafini
Finally, one patent reported the use of bryostatin-1, a substance from the marine benthic animal Bugula neritinac, to treat SARS-CoV-1. This is the first macrolide compound with anti-cancer activity, having strong therapeutic properties in the treatment of leukemias, renal, cervical cancers, melanoma, and lymphomas. It can also be used to treat atypical pneumonia present in the clinical picture of CoVs [72].
Clinical pharmacology in HIV cure research – what impact have we seen?
Published in Expert Review of Clinical Pharmacology, 2019
Andrea Giacomelli, Sonia de Rose, Stefano Rusconi
Other key molecular mechanisms involved in HIV-1 latency are sequestration of transcription initiation/elongation factors and blockade of the assembly of the active elongation factor, P-TEFb. The NF-κB pathway appears to be one of the most relevant pathways concerning HIV-1 reactivation. Protein kinase C agonists (PKCA) activate PKC isoforms which then phosphorylate IκB and consequently activate NF-κB. Several PKC agonists have been considered for purging the reservoirs of latent HIV-1 [61]. First of all, prostratin is a unique phorbol ester that it induces potent T cell activation signals and is not tumorigenic. Besides the ability of prostratin to induce T-cell activation through PKC, without tumor-promoting ability, another unique property is that, despite being able to reactivate latent HIV-1, it exerts an inhibitory effect on active HIV-1 replication through downregulation of CD4 [62]. Furthermore, bryostatin-1 has appeared to be an effective reversing agent. Bryostatins represent an important group of pharmaceutically promising substances. These compounds are produced by commensal microorganisms naturally occurring in marine invertebrates, mainly in bryozoans. The most frequently investigated substance is bryostatin-1, which is a highly oxygenated macrolide with a polyacetate backbone [63]. Its mechanism of action involves a bound to the diacylglycerol-binding region within the C-1 regulatory domain of PKC. Bryostatin-1 has shown to reactivate latent HIV-1 in vitro in monocytoid and lymphoid cell line models of latency and was approximately 1,000-fold more potent than prostratin [62]. However, since economic and environmental factors have severely limited its availability, De Cristopher et al. reported the activity of seven bryostatin-1 analogs, dubbed ‘bryologs’, specifically designed to obtain molecules easier to operate with. These compounds incorporate a tetrahydropyranyl B-ring formed through a versatile prins macrocyclization. They demonstrated that these simplified bryostatin analogs, which share the functional activity of the clinical candidate prostratin, are up to four orders of magnitude more potent [64].
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