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The enediynes are a class of cyclic molecules whose core ring contains an alkene conjugated to two alkynes.[1] This core ring consists of a total of either nine or ten members.[2] Other functional groups are usually attached to the nine- or ten-membered ring, providing each enediyne with additional chemical properties.

Since the discovery of calicheamicin and esperamicin in 1987, several more enediynes have been discovered as natural products in bacteria.[3] Synthetic enediynes have also been designed to improve the functionality of the naturally occurring enediynes.

Enediynes are most notable for their limited use as antitumor antibiotics. They are efficient at inducing apoptosis in cells, but cannot differentiate cancerous cells from healthy cells. Consequently, research is being conducted to increase the specificity of enediyne toxicity.

Structure and Reactivity

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A nine- or ten-membered ring containing a double bond between two triple bonds is termed the warhead of the enediyne. In this state, the warhead is inactive. Enediynes are triggered into a chemically active state via Bergman or Myers-Saito cyclization. The triggering mechanism can be attributed to an intramolecular nucleophilic attack initiated by one of the variable regions of the molecule. Triggering can also occur via attack by an external nucleophile.

Electron pushing that occurs during Bergman cyclization in a generic enediyne molecule. A 1,4-benzenoid diradical fused to another ring is the result.

Bergman cyclization restructures the enediyne ring into two smaller rings. One electron from each of the enediyne triple bonds is pushed to the adjacent single bonds, generating two new double bonds. Meanwhile, another pair of electrons (one from each alkyne) is used form a new covalent bond. The resulting formation is a 1,4-benzenoid diradical fused to a ring comprised of the leftover atoms from the original enediyne.

Some enediynes have an epoxide group attached to their ring, making Bergman cyclization unfavorable due to steric hindrance. For Bergman cyclization to occur, the epoxide must be removed.

A generic enediyne molecule is pictured above. During Myers-Saito cyclization, electrons pushing begins at the diene and generates an unstable cumulene. This cumulene and the nearby alkyne donate one electron to split the enediyne ring into two fused rings.

Myers-Saito cyclization is another triggering mechanism by which an enediyne warhead becomes a diradical. This mechanism requires the alkene of the enediyne to be part of a diene with a double bond in a variable group. A nucleophile will attack the double bond in the variable region, causing a chain reaction of electron pushing. Ultimately, one of the triple bonds of the enediyne is converted to a cumulene.[4] The cumulene and the remaining alkyne donate one electron each to form a new covalent bond.

The diradicals generated by Bergman and Myers-Saito cyclization are highly reactive.

Classes of Enediynes

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There are fourteen naturally occurring enediynes.[5] The other existing classes of enediynes have been synthesized in the lab.

Enediynes have been split into two sub-families: those with nine members in the core enediyne ring and those with ten-membered rings.

Nine-Membered Enediyne Rings (Chromoproteins)

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The nine-membered enediynes are also referred to as chromoproteins because they have an attached protein as a variable group. This protein is necessary for transport and stabilization of the enediyne group.[6]

Neocarzinostatin

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Neocarzinostatin is a natural product of Streptomyces carzinostaticus. It forms an apoprotein with a 113-amino acid polypeptide which can cleave histone protein H1.[7] Neocarzinostatin is an example of an enediyne that undergoes triggering via Myers-Saito cyclization. An analog of neocarzinostatin, SMANCS, has been approved for use in Japan as an antitumor drug for liver cancer.[8]

C-1027

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Also known as lidamycin, C-1027 is one of the most potent antitumor enediynes. C-1027 was first isolated from Streptomyces globisporus in a soil sample taken from the Qian-Jiang District of China. Unlike most enediynes, C-1027 does not undergo a triggering process to become an activated 1,4-benzenoid diradical.[9] C-1027 has demonstrated potential efficacy against hypoxic tumors.[10]

Ten-Membered Enediyne Rings

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Calicheamicins

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The calicheamicins are a sub-family of enediynes that were isolated from Micromonospora echinospora calichensis.[11] All calicheamicin family members demonstrate potent antimicrobial activity against Gram-positive and Gram-negative organisms.[11] Calicheamicn γ1 exhibited significant antitumor activity against leukemia and melanoma cells in vivo.[11] The calicheamicins are notably similar in structure to the esperamicins.

Esperamicins

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The esperamicins are a sub-family of enediynes that are considered among the most potent antitumor antibiotics discovered.[12] First isolated in Actinomadura verrucosospora, members of the esperamicin family include esperamicin A1, A1b, A2, A3, A4, B1, B2, and X. Esperamicin X is an inactive esperamicin naturally produced by A. verrucosospora.[12] Compounds with thiol groups induce triggering among the esperamicins.[13]

Dynemicins

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The dynemicins are a sub-family of enediynes whose members are organic compounds generated in Micromonospora chersina.[6] Dynemicin A was the first member of this sub-family to be discovered. It was isolated from M. chersina in a soil sample taken from the state of Gujarat in India.[14] Dynemicins are violet in color because they contain anthraquinone as a variable group attached to the enediyne core.[6] Dynemycins have demonstrated strong antitumor activity against leukemia and melanoma cells.[15]

Golfomycin A

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Golfomycin A is a synthetic enediyne molecule designed in an attempt to create a more easily manufactured antitumor antibiotic.[16] DNA strand-scission induced by golfomycin A is pH dependent.[16] Preliminary in vitro studies have demonstrated that golfomycin A can reduce carcinomas in bladder cells.[16]

See also

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References

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  1. ^ Nicolaou, K. C.; Smith, A. L.; Yue, E. W. (1993-07-01). "Chemistry and biology of natural and designed enediynes". Proceedings of the National Academy of Sciences. 90 (13): 5881–5888. doi:10.1073/pnas.90.13.5881. ISSN 0027-8424. PMID 8327459.
  2. ^ Galm, Ute; Hager, Martin H.; Van Lanen, Steven G.; Ju, Jianhua; Thorson, Jon S.; Shen, Ben (2005). "Antitumor Antibiotics:  Bleomycin, Enediynes, and Mitomycin". Chemical Reviews. 105 (2): 739–758. doi:10.1021/cr030117g. ISSN 0009-2665. {{cite journal}}: no-break space character in |title= at position 23 (help)
  3. ^ Lee, May D.; Dunne, Theresa S.; Siegel, Marshall M.; Chang, Conway C.; Morton, George O.; Borders, Donald B. (May 1987). "Calichemicins, a novel family of antitumor antibiotics. 1. Chemistry and partial structure of calichemicin .gamma.1I". Journal of the American Chemical Society. 109 (11): 3464–3466. doi:10.1021/ja00245a050. ISSN 0002-7863.
  4. ^ "Bergman Cyclization". www.organic-chemistry.org. Retrieved 2018-05-05.
  5. ^ Shen, Ben; Hindra; Yan, Xiaohui; Huang, Tingting; Ge, Huiming; Yang, Dong; Teng, Qihui; Rudolf, Jeffrey D.; Lohman, Jeremy R. (2015). "Enediynes: Exploration of microbial genomics to discover new anticancer drug leads". Bioorganic & Medicinal Chemistry Letters. 25 (1): 9–15. doi:10.1016/j.bmcl.2014.11.019. ISSN 0960-894X. PMC 4480864. PMID 25434000.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ a b c Gao, Qunjie; Thorson, Jon S. (2008-05-01). "The biosynthetic genes encoding for the production of the dynemicin enediyne core in Micromonospora chersina ATCC53710". FEMS Microbiology Letters. 282 (1): 105–114. doi:10.1111/j.1574-6968.2008.01112.x. ISSN 0378-1097. PMC 5591436. PMID 18328078.{{cite journal}}: CS1 maint: PMC format (link)
  7. ^ Heyd, Bernadette; Lerat, Guilhem; Adjadj, Elisabeth; Minard, Philippe; Desmadril, Michel (2000). "Reinvestigation of the Proteolytic Activity of Neocarzinostatin". Journal of Bacteriology. 182 (7): 1812–1818. ISSN 0021-9193. PMID 10714984.
  8. ^ Maeda, H. (2001-03-01). "SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy". Advanced Drug Delivery Reviews. 46 (1–3): 169–185. ISSN 0169-409X. PMID 11259839.
  9. ^ Xu, Y.; Zhen, Y.; Goldberg, Irving H. (1994-05-17). "C1027 Chromophore, a Potent New Enediyne Antitumor Antibiotic, Induces Sequence-Specific Double-Strand DNA Cleavage". Biochemistry. 33 (19): 5947–5954. doi:10.1021/bi00185a036. ISSN 0006-2960.
  10. ^ Chen, Yihua; Yin, Min; Horsman, Geoff P.; Shen, Ben (2011-03-25). "Improvement of the Enediyne Antitumor Antibiotic C-1027 Production by Manipulating Its Biosynthetic Pathway Regulation inStreptomyces globisporus". Journal of Natural Products. 74 (3): 420–424. doi:10.1021/np100825y. ISSN 0163-3864. PMC 3064734. PMID 21250756.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ a b c Maiese, W. M.; Lechevalier, M. P.; Lechevalier, H. A.; Korshalla, J.; Kuck, N.; Fantini, A.; Wildey, M. J.; Thomas, J.; Greenstein, M. (April 1989). "Calicheamicins, a novel family of antitumor antibiotics: taxonomy, fermentation and biological properties". The Journal of Antibiotics. 42 (4): 558–563. ISSN 0021-8820. PMID 2722671.
  12. ^ a b Golik, Jerzy; Clardy, Jon; Dubay, George; Groenewold, Gary; Kawaguchi, Hiroshi; Konishi, Masataka; Krishnan, Bala; Ohkuma, Hiroaki; Saitoh, Kyoichiro (May 1987). "Esperamicins, a novel class of potent antitumor antibiotics. 2. Structure of esperamicin X". Journal of the American Chemical Society. 109 (11): 3461–3462. doi:10.1021/ja00245a048. ISSN 0002-7863.
  13. ^ Sugiura, Y; Uesawa, Y; Takahashi, Y; Kuwahara, J; Golik, J; Doyle, T W (October 1989). "Nucleotide-specific cleavage and minor-groove interaction of DNA with esperamicin antitumor antibiotics". Proceedings of the National Academy of Sciences of the United States of America. 86 (20): 7672–7676. ISSN 0027-8424. PMID 2813351.
  14. ^ Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H.; VanDuyne, G. D. (September 1989). "Dynemicin A, a novel antibiotic with the anthraquinone and 1,5-diyn-3-ene subunit". The Journal of Antibiotics. 42 (9): 1449–1452. ISSN 0021-8820. PMID 2793600.
  15. ^ Unno, Ryoichi; Michishita, Hisashi; Inagaki, Hideaki; Suzuki, Yoko; Baba, Yutaka; Jomori, Takahito; Nishikawa, Toshio; Isobe, Minoru (May 1997). "Synthesis and antitumor activity of water-soluble enediyne compounds related to dynemicin a". Bioorganic & Medicinal Chemistry. 5 (5): 987–999. doi:10.1016/s0968-0896(97)00037-0. ISSN 0968-0896.
  16. ^ a b c Nicolaou, K. C.; Skokotas, Golfo; Furuya, S.; Suemune, H.; Nicolaou, D. Colette (September 1990). "Golfomycin A, a Novel Designed Molecule with DNA-Cleaving Properties and Antitumor Activity". Angewandte Chemie International Edition in English. 29 (9): 1064–1067. doi:10.1002/anie.199010641. ISSN 0570-0833.
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