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| Names | |
|---|---|
| IUPAC name Methyl {(1R,4Z,8S,13Z)-8-({6-deoxy-2-O-[2,4-dideoxy-4-(isopropylamino)-3-O-methyl-α-L-threo-pentopyranosyl]-4-C-[(6-hydroxy-9H-β-carbolin-1-yl)carbonyl]-4-S-methyl-4-thio-β-D-galactopyranosyl}oxy)-1-hydroxy-13-[2-(methyltrisulfanyl)ethylidene]-11-oxobicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-10-yl}carbamate | |
| Identifiers | |
3D model (JSmol) | |
| ChemSpider | |
| |
| |
| Properties | |
| C46H52N4O12S4 | |
| Molar mass | 981.18 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Shishijimicin A is anenediyne antitumor antibiotic isolated fromDidemnum proliferum.[1] Isolated in 2003[2] it is part of the family of 10 member ringedenediyne antitumor antibiotic agents, which includes: namenamicin,esperamicin and,calicheamicin. Due to its high potency fromcytotoxicity, Shishjimicin A is currently undergoing testing as a possibleAntibody-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”,[3] also known asPaclitaxel, 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.
Thetotal synthesis of shishjimicin A was published by scientists at Rice University in 2015,[4] led byK. C. Nicolaou. Using methodology from the previous isolation ofcalicheamicin,[5] 21 total steps were conducted for the synthesis,[6][4] briefly outlined below:
The total synthesis includes:[6]
The goal of the synthesis is to create two complex intermediate compounds, trichloroacetimidate and hydroxyenediyne. These will be coupled to produce shishjiimicin A. Though this organic synthesis is challenging, its mapping allows for future contribution to research efforts. Further improvements of the coupling reaction are currently being studied. Practicality and synthesis variations of the complex molecule are essential to working alongside pharmaceutical companies to develop clinical trials and treatment options.
Shishijimicin A binds to the minor groove of double-stranded DNA (DsDNA) where its β-carboline moiety intercalates into the DNA.[2] The unbound linker regions of DNA in the process ofinterphase andmetaphase are open to binding by binders such as shishijimicin A. These regions lack protectivehistone proteins throughout the eukaryotic cell cycle. This dsDNA cleavage and low selection probability for sequences by shishijimicin A may attribute to its cytotoxic properties.[2]
Shishijimicin A exhibits cytotoxicity towardsHeLa cells, withIC50 values between 1.8 and 6.9 pM.[7]
