Cryptophycins are a family of macrolide molecules that are potent cytotoxins and have been studied for potential antiproliferative properties useful in developing chemotherapy. They are members of the depsipeptide family.
Cryptophycins are a family of macrolide molecules that are potent cytotoxins and have been studied for potential antiproliferative properties useful in developing chemotherapy. They are members of the depsipeptide family.
Cryptophycins were originally discovered in 1990 in cyanobacteria of the genus Nostoc . [1] Cryptophycins were patented as antifungal agents with an unknown mechanism of action and subsequently identified as microtubule inhibitors. [2] Closely related molecules were reported in the marine sponge Dysidea arenaria , which were first given the name arenastatins. [3] However, since cyanobacteria are common symbionts of sponges, it has been suggested that bacteria may be the true origin in cases where sponge and bacterial metabolites closely resemble one another. [4] Nevertheless, study of the structure-activity relationships between the two subgroups of molecules led to improved understanding of their cytotoxic effects. [5] : 230
Cryptophycins are potent microtubule inhibitors, with a mechanism of action similar to that of vinca alkaloids. [2] [6] [7] Treatment of cells with cryptophycins depletes microtubules through interaction with tubulin, thereby preventing cell division. [8] Cryptophycins are capable of inducing apoptosis, [9] possibly through other mechanisms in addition to that mediated by microtubule inhibition. [10]
Members of the cryptophycin family have been studied as anti-tumor agents. Cryptophycin-52, a synthetic analog of natural product cryptophycins also known as LY355703, [11] reached phase II clinical trials but was withdrawn due to side effects. [12]
Cryptophycins were first isolated from cyanobacteria but have subsequently been produced by chemical synthesis. [13] [14] Chemoenzymatic syntheses have also been reported. [15] [16]
Noscapine, also known as narcotine, nectodon, nospen, anarcotine and (archaic) opiane, is a benzylisoquinoline alkaloid of the phthalideisoquinoline structural subgroup, which has been isolated from numerous species of the family Papaveraceae. It lacks effects associated with opioids such as sedation, euphoria, or analgesia (pain-relief) and lacks addictive potential. Noscapine is primarily used for its antitussive (cough-suppressing) effects.
Bryostatins are a group of macrolide lactones from the marine organism Bugula neritina that were first collected and provided to JL Hartwell’s anticancer drug discovery group at the National Cancer Institute (NCI) by Jack Rudloe. Bryostatins are potent modulators of protein kinase C. They have been studied in clinical trials as anti-cancer agents, as anti-AIDS/HIV agents and in people with Alzheimer's disease.
Vinblastine (VBL), sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. This includes Hodgkin's lymphoma, non-small-cell lung cancer, bladder cancer, brain cancer, melanoma, and testicular cancer. It is given by injection into a vein.
Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.
A depsipeptide is a peptide in which one or more of its amide, -C(O)NHR-, groups are replaced by the corresponding ester, -C(O)OR-. Many depsipeptides have both peptide and ester linkages. Elimination of the N–H group in a peptide structure results in a decrease of H-bonding capability, which is responsible for secondary structure and folding patterns of peptides, thus inducing structural deformation of the helix and β-sheet structures. Because of decreased resonance delocalization in esters relative to amides, depsipeptides have lower rotational barriers for cis-trans isomerization and therefore they have more flexible structures than their native analogs. They are mainly found in marine and microbial natural products.
Rhizoxin is an antimitotic agent with anti-tumor activity. It is isolated from the fungus Rhizopus microsporus which causes rice seedling blight.
A mitotic inhibitor, microtubule inhibitor, or tubulin inhibitor, is a drug that inhibits mitosis, or cell division, and is used in treating cancer, gout, and nail fungus. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow through continuous division that eventually spread through the body (metastasize). Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are also used in cytogenetics, where they stop cell division at a stage where chromosomes can be easily examined.
Eribulin, sold under the brand name Halaven among others, is an anti-cancer medication used to treat breast cancer and liposarcoma.
Salinomycin is an antibacterial and coccidiostat ionophore therapeutic drug.
Halichondrin B is a polyether macrolide originally isolated from the marine sponge Halichondria okadai by Hirata and Uemura in 1986. In the same report, these authors also reported the exquisite anticancer activity of halichondrin B against murine cancer cells both in culture and in in vivo studies. Halichondrin B was highly prioritized for development as a novel anticancer therapeutic by the United States National Cancer Institute and, in 1991, was the original test case for identification of mechanism of action by NCI's then-brand-new "60-cell line screen"
Romidepsin, sold under the brand name Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis. It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, a part of Celgene.
Symplocamide A is a newly discovered (2008) 3-amino-6-hydroxy-2-piperidone (Ahp) cyclodepsipeptide that has been isolated from a marine cyanobacteria in Papua New Guinea, which has only been identified at the genus level (Symploca). Cyanobacteria, both freshwater and marine, are known as producers of diverse protease inhibitors that may be used to treat diseases, such as HIV, and some forms of cancer. Research on symplocamide A has shown that it is a strong serine protease inhibitor and has a high level of cytotoxicity to cancer cells when used in vitro. As of the time of this writing, its use as a treatment on human participants has not been done and future study will have to be done before any human testing can be commenced.
FL3 is a synthetic flavagline that displays potent anticancer and cardioprotectant activities. This compound induces the death of cancer cells by an original mechanism that involves the apoptosis-inducing factor and caspase 12, suggesting that it may improve the efficacy of cancer chemotherapies. It was also shown that FL3 may enhance the efficacy of one of the most widely used anticancer agents, doxorubicin, and alleviate its main adverse effect, cardiac damage.
Taccalonolides are a class of microtubule-stabilizing agents isolated from Tacca chantrieri that has been shown to have selective cancer-fighting properties. Other examples of microtubule-stabilizing agents include taxanes and epothilones, both of which prevent cancer cells from dividing by interfering with tubulin. While taxanes like paclitaxel and docetaxel have been used successfully against breast, ovarian, prostate, and non–small-cell lung cancers, intrinsic and acquired drug resistance limit their anticancer properties. Unlike taxanes, taccalonolides appear to work through a different mechanism of action that does not involve tubulin, although recently isolated taccalonolides AF and AJ have shown tubulin-interaction activity. The discovery of taccalonolides opens up new possibilities to treat cancer cells, especially ones that are taxane- or epithilone-resistant.
Curacin A is a hybrid polyketide synthase (PKS)/nonribosomal peptide synthase (NRPS) derived natural product produced isolated from the cyanobacterium Lyngbya majuscula. Curacin A belongs to a family of natural products including jamaicamide, mupirocin, and pederin that have an unusual terminal alkene. Additionally, Curacin A contains a notable thiazoline ring and a unique cyclopropyl moiety, which is essential to the compound's biological activity. Curacin A has been characterized as potent antiproliferative cytotoxic compound with notable anticancer activity for several cancer lines including renal, colon, and breast cancer. Curacin A has been shown to interact with colchicine binding sites on tubulin, which inhibits microtubule polymerization, an essential process for cell division and proliferation.
Dysidea arenaria is a species of marine sponge (poriferan) found in the Pacific Ocean. It is a member of the order Dictyoceratida, one of two sponge orders that make up the keratose or "horny" sponges in which a mineral skeleton is absent and a skeleton of organic fibers is present instead.
Coibamide A is an antiproliferative depsipeptide. It comes from the Leptolyngbya cyanobacterium.
Swinholides are dimeric 42 carbon-ring polyketides that exhibit a 2-fold axis of symmetry. Found mostly in the marine sponge Theonella, swinholides encompass cytotoxic and antifungal activities via disruption of the actin skeleton. Swinholides were first described in 1985 and the structure and stereochemistry were updated in 1989 and 1990, respectively. Thirteen swinholides have been described in the literature, including close structural compounds such as misakinolides/bistheonellides, ankaraholides, and hurgholide A It is suspected that symbiotic microbes that inhabit the sponges rather than the sponges themselves produce swinholides since the highest concentration of swinholides are found in the unicellular bacterial fraction of sponges and not in the sponge fraction or cyanobacteria fraction that also inhabit the sponges.
Valerie J. Paul is the Director of the Smithsonian Marine Station at Fort Pierce, in Fort Pierce, FL since 2002 and the Head Scientist of the Chemical Ecology Program. She is interested in marine chemical ecology, and specializes in researching the ecology and chemistry of Cyanobacteria, blue-green algae, blooms. She has been a fellow of the American Association for the Advancement of Science since 1996, and was the chairperson of the Marine Natural Products Gordon Research Conference in 2000.
Laucysteinamide A (LcA) is a marine natural product isolated from a cyanobacterium, Caldora penicillata.
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