The Masamune-Bergman cyclization or Masamune-Bergman reaction or Masamune-Bergman cycloaromatization is an organic reaction and more specifically a rearrangement reaction taking place when an enediyne is heated in presence of a suitable hydrogen donor. It is the most famous and well-studied member of the general class of cycloaromatization reactions. It is named for Japanese-American chemist Satoru Masamune and American chemist Robert G. Bergman. The reaction product is a derivative of benzene.
Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.
The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "caliche pits", located in Kerrville, Texas. The sample was collected by a scientist working for Lederle Labs. It is extremely toxic to all cells and, in 2000, a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide calicheamicin was developed and marketed as targeted therapy against the non-solid tumor cancer acute myeloid leukemia (AML). A second calicheamicin-linked monoclonal antibody, inotuzumab ozogamicin an anti-CD22-directed antibody-drug conjugate, was approved by the U.S. Food and Drug Administration on August 17, 2017, for use in the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Calicheamicin γ1 and the related enediyne esperamicin are the two of the most potent antitumor agents known.
Pixantrone is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewer toxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.
Robert George Bergman is an American chemist. He is Professor of the Graduate School and Gerald E. K. Branch Distinguished Professor Emeritus at the University of California, Berkeley.
Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata, a tree native to China used in traditional Chinese medicine. It has been used clinically more recently in China for the treatment of gastrointestinal tumors. CPT showed anticancer activity in preliminary clinical trials, especially against breast, ovarian, colon, lung, and stomach cancers. However, it has low solubility and adverse effects have been reported when used therapeutically, so synthetic and medicinal chemists have developed numerous syntheses of camptothecin and various derivatives to increase the benefits of the chemical, with good results. Four CPT analogues have been approved and are used in cancer chemotherapy today, topotecan, irinotecan, belotecan, and trastuzumab deruxtecan. Camptothecin has also been found in other plants including Chonemorpha fragrans.
Indolocarbazoles (ICZs) are a class of compounds that are under current study due to their potential as anti-cancer drugs and the prospective number of derivatives and uses found from the basic backbone alone. First isolated in 1977, a wide range of structures and derivatives have been found or developed throughout the world. Due to the extensive number of structures available, this review will focus on the more important groups here while covering their occurrence, biological activity, biosynthesis, and laboratory synthesis.
In organic chemistry, enediynes are organic compounds containing two triple bonds and one double bond.
Micromonospora echinospora is a species of bacteria that is known for producing the enediyne antibiotic calicheamicins.
Kinamycins are a group of bacterial polyketide secondary metabolites containing a diazo group. Kinamycins are known for their cytotoxicity and are considered of interest for potential use in anti-cancer therapies.
Bohemic acid is a mixture of chemical compounds which is obtained through fermentation by actinobacteria species in the genus Actinosporangium (Actinoplanaceae). The name honors the Puccini opera La Bohème and many individual components of the acid carry the names of characters from La Bohème. Most of those components are antitumor agents and anthracycline antibiotics active against Gram-positive bacteria.
Dynemicin A is an anti-cancer enediyne drug. It displays properties which illustrate promise for cancer treatments, but still requires further research.
The duocarmycins are members of a series of related natural products first isolated from Streptomyces bacteria in 1978. They are notable for their extreme cytotoxicity and thus represent a class of exceptionally potent antitumour antibiotics.
2-Amino-4-deoxychorismate dehydrogenase is an enzyme with systematic name (2S)-2-amino-4-deoxychorismate:FMN oxidoreductase. This enzyme catalyses the following chemical reaction
Free radical damage to DNA can occur as a result of exposure to ionizing radiation or to radiomimetic compounds. Damage to DNA as a result of free radical attack is called indirect DNA damage because the radicals formed can diffuse throughout the body and affect other organs. Malignant melanoma can be caused by indirect DNA damage because it is found in parts of the body not exposed to sunlight. DNA is vulnerable to radical attack because of the very labile hydrogens that can be abstracted and the prevalence of double bonds in the DNA bases that free radicals can easily add to.
Neothramycin A and B are stereoisomeric antibiotics with anticancer activity. The stereoisomers are interchangeable in aqueous solution and the antibiotic, Neothramycin, contains both in approximately equal amounts. They belong to the pyrrolo(1,4)benzodiazepine, or anthramycin, group which includes other antibiotics such as anthramycin, tomaymycin, and sibiromycin. Neothramycin was originally isolated from Streptomyces No. MC916-C4, a cycloheximide-producing strain, by Umezawa et al. Subsequent testing has shown its capabilities as an anticancer drug, antiprotozoal drug, and even possible uses in DNA fluorescence based assays. Its activities against cancer warranted phase I testing of the drug. More recently, in 1991, anthramycin derivatives, which are very similar to neothramycin, have been investigated for their ability to link DNA when dimerized. These compounds were tested using a fluorescence based assay. These compounds showed an ability to bind dG-containing DNA duplexes with high specificity. This specificity of a DNA crosslinking agent is highly sought after since most are electrophiles and bind indiscriminately. The data collected also showed that pyrrolo(1,4)benzodiazepines can also be used to measure the fluorescence polarization anisotropy on the 0.1-100 ns time scale.
Kedarcidin is a chromoprotein antitumor antibiotic first isolated from an Actinomycete in 1992, comprising an ansa-bridged enediyne chromophore (shown) as well as an apoprotein that serves to stabilize the toxin in the Actinomycete. Like other members of the enediyne class of drugs—so named for the nine-or-ten-membered core structure bearing an alkene directly attached to two alkynyl appendages—kedarcidin was likely evolved to kill bacteria that compete with the producing organism. Because it achieves this by causing DNA damage, however, kedarcidin is capable of harming tumor cells, as well. Kedarcidin is thus the subject of scientific research, both for its structural complexity as well as its anticancer properties.
Azinomycin B is a natural product that contains densely assembled functionalities with potent antitumor activity. It is isolated from Streptomyces sahachiroi which is reisolated from S. griseofuscus along with its analog azinomycin A. Azinomycin B can bind within the major groove of DNA and forms covalent interstrand crosslinks (ISCs) with the purine bases. The DNA alkylation and crosslinking by azinomycin B suggests its potent antitumor activity.
C-1027 or Lidamycin is an antitumor antibiotic consisting of a complex of an enediyne chromophore and an apoprotein. It shows antibiotic activity against most Gram-positive bacteria. It is one of the most potent cytotoxic molecules known, due to its induction of a higher ratio of DNA double-strand breaks than single-strand breaks.
Shishijimicin A is an enediyne antibiotic isolated from Didemnum proliferum. Isolated in 2003 it is part of the family of 10 member ringed enediyne antitumor antibiotic agents, which includes: namenamicin, esperamicin and, calicheamicin. Due to its high potency from cytotoxicity, Shishjimicin A is currently undergoing testing as a possible Antibody-antibiotic Conjugate (ADCs) cancer treatment. Laboratory tests indicate it to be “more than 1,000 times as toxic to cancer cells as the anticancer drug taxol”, also known as Paclitaxel, a prevalent chemotherapy medication. As such, theoretically, only an administration of a minuscule dose of the molecule would be necessary per each treatment. As shishjimicin A supply is scarce and the full extent of its side effects is not yet established, there is still a need for further biological and clinical studies.
