Cylindrocyclophanes

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Cylindrocyclophanes are a class of cyclophane, a group of aromatic hydrocarbons composed of two benzene rings attached in a unique structure. Cylindrocyclophanes were the first cyclophanes found in nature, isolated from a species of cyanobacteria, and have proven to be an interesting group of compounds to study due to their unusual molecular structure and intriguing biological possibilities, especially its cytotoxicity to some cancer cell lines.

Origin

Before the cylindrocyclophanes, the cyclophanes had all been produced synthetically. However, when a culture of the cyanobacteria Cylindrospermum lichenforme was being evaluated for antitumor activity, the extract was analyzed for new compounds, and a [7,7] paracyclophane was discovered. The structure of the cyclophane was determined and cylindrocyclophane A was named.[1] A related class of compounds, the nostocyclophanes, were discovered during the same study but from another species of cyanobacteria, the Nostoc linckia. In a later study on the cytotoxicity of cyanobacterial compounds, an additional related class of compounds was discovered, the carbamidocyclophanes, from a Vietnamese species of Nostoc sp.[2]

Structure

Cylindrocyclophanes are all [7,7] paracyclophanes, differing only in the functional groups present on C-1, C-14, C-29, and C-33. There are currently 16 cylindrocyclophanes that have been identified: cylindrocyclophanes A - F,[3] A4 - A1, C4 - C1, F4, and AB4.[4]

Cylindrocyclophanes A-F differ only in the functional groups present on C-1 (R1) and C-14 (R3), and the only functional groups present are hydroxyl (OH) and acetoxy (OAc) groups. Cylindrocyclophanes A4 - A1, C4 - C1, F4, and AB4 also have functional groups on C-29 (R4) and C-33 (R2) and differ from cylindrocyclophanes A-F mainly in their halogenated functional groups. See the following table for a complete list of functional groups for the known cylindrocyclophanes:

Cylindrocyclophane R1 R2 R3 R4
A OH H OH H
B OH H OAc H
C OH H H H
D OAc H OAc H
E OAc H H H
F H H H H
A4 OH CHCl2 OH CHCl2
A3 OH CH2Cl OH CHCl2
A2 OH CH3 OH CHCl2
A1 OH CH3 OH CH2Cl
C4 OH CHCl2 H CHCl2
C3 OH CH2Cl H CHCl2
C2 OH CH3 H CHCl2
C1 OH CH3 H CH2Cl
F4 H CHCl2 H CHCl2
AB4 OH CHBr2 OH CHBr2

Cytotoxicity

When cylindrocyclophane A was discovered, it was during an evaluation of the cyanobacteria Cylindrospermum lichenforme for antitumor activity.[1] It was shown that Cylindrospermum lichenforme did indeed have moderate cytotoxicity again the KB and LoVo tumor cell lines, and this was attributed to cylindrocyclophane A. However, this cytotoxicity is not reserved only for tumor cells, which may limit its ability to be developed pharmaceutically.[5] Since, as stated by Bui, et al., "cyanobacteria have been identified as one of the most promising sources of highly complex natural products"[2] due to their biological activities, more insight has been gained into the mechanism behind the cylindrocyclophanes' cytotoxicity.

A team at the University of Illinois-Chicago studied the cytotoxicity of the cylindrocyclophanes further and determined that they act mainly as proteasome inhibitors., specifically inhibiting the 20S proteasome.[4] Since the function of the proteasome is to break down damaged or unnecessary proteins, it is extremely important to the cells' ability to continue to proliferate. When the proteasome does not perform its function, apoptosis can result. The team at University of Illinois-Chicago determined that cylindrocyclophanes A4, A3, and A2 displayed the highest cytotoxicity, which they attributed to the dichloromethyl functional group present at R4. When the cytotoxicity of cylindrocyclophanes A, C, F were examined, A was twice as effective as C, which was attributed to its two hydroxyl functional groups compared to only one for C and none for F. When the effectiveness of the dichloromethyl and hydroxyl functional groups were examined together, it was determined that the most effective arrangement was to have the dichloromethyl and hydroxyl groups "adjacent" spatially to each other.

Synthesis

Since the cylindrocyclophanes have such a unique structure and exciting biological possibilities due to their cytotoxicity, there have been numerous efforts to create them synthetically in the laboratory. One of the first attempts was the total synthesis of cylindrocyclophane F, which was accomplished in 20 steps with a 8.3% yield.[6] This, along with other syntheses of cylindrocyclophanes, relies on multistep reaction mechanisms, typically employing Myers reductive coupling and Kowalski ester homologation to obtain the beginning resorcinol fragments and Danheiser benzannulation to construct the aromatic rings with multiple functional groups.[5] After the first total synthesis of cylindrocyclophane F, total synthesis of cylindrocyclophanes A and F were accomplished using a new olefin metathesis dimerization cascade. For synthesis of cylindrocyclophane F, this reduced the number of steps to 11 and increased the yield to 22%. This process was also able to be applied to the synthesis of cylindrocyclophane A in a 16-step reaction with a 8.1% yield.[7] Significant increase in yield was accomplished when a head-to-tail cyclodimerization was paired with a Ramberg-Bäcklund reaction, resulting in a yield of 71% for A and 74% for F.[8]

References

  1. ↑ 1.0 1.1 Moore, Bradley S.; Chen, Jian Lu; Patterson, Gregory M. L.; Moore, Richard E.; Brinen, Linda S.; Kato, Yoko; Clardy, Jon (1990). "[7.7]Paracyclophanes from blue-green algae". J. Am. Chem. Soc. 112 (10): 4061–4063. doi:10.1021/ja00166a066. 
  2. ↑ 2.0 2.1 Bui, Ha T. N.; Jansen, Rolf; Pham, Hang T. L.; Mundt, Sabine (2007). "Carbamidocyclophanes A-E, Chlorinated Paracyclophanes with Cytotoxic and Antibiotic Activity from the Vietnamese Cyanobacterium Nostoc sp.". Journal of Natural Products 70 (4): 499–503. doi:10.1021/np060324m. 
  3. ↑ Moore, Bradley S.; Chen, Jian-Lu; Patterson, Gregory M. L.; Moore, Richard E. (1992). "Structures of Cylindrocyphanes a-f". Tetrahedron 48 (15): 3001–3006. doi:10.1016/S0040-4020(01)92244-6. 
  4. ↑ 4.0 4.1 Chlipala, George E.; Sturdy, Megan; Krunic, Aleksej; Lantvit, Daniel D.; Shen, Qi; Porter, Kyle; Swanson, Steven M.; Orjala, Jimmy (2010). "Cylindrocyclophanes with Proteasome Inhibitory Activity from the Cyanobacterium Nostoc sp.". Journal of Natural Products 73 (9): 1529–1537. doi:10.1021/np100352e. 
  5. ↑ 5.0 5.1 Siska, Sarah. A scrutiny of the total synthesis of (-)-Cylindrocyclophane F [PDF document]. Retrieved from the Department of Chemistry and Chemical Biology at Harvard University web site: http://www2.lsdiv.harvard.edu/labs/evans/pdf/smnr_1999-2000_Siska_Sarah.pdf
  6. ↑ Smith, Amos B.; Kozmin, Sergey A.; Paone, Daniel V. (1999). "Total Synthesis of (-)-Cylindrocyclophane F". J. Am. Chem. Soc. 121 (32): 7423–7424. doi:10.1021/ja991538b. 
  7. ↑ Smith, Amos B.; Adams, Christopher M.; Kozmin, Sergey A.; Paone, Daniel V. (2001). "Total Synthesis of (-)-Cylindrocyclophanes A and F Exploiting the Reversible Nature of the Olefin Cross Metathesis Reaction". J. Am. Chem. Soc. 123 (25): 5925–5937. doi:10.1021/ja0106164. 
  8. ↑ Nicolaou, K. C.; Sun, Ya-Ping; Korman, Henry; Sarlah, David (2010). "Asymmetric Total Synthesis of Cylindrocyclophanes A and F through Cyclodimerization and a Ramberg-Bäcklund Reaction". Angewandte Chemie 49 (34): 5875–5878. doi:10.1002/anie.201003500. 
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