Total Synthesis of Ciguatoxin CTX3C

Hirama, Masahiro; Oishi, Tohru; Uehara, Hisatoshi; Inoue, M.; Maruyama, Megumi; Oguri, Hiroki; Satake, Masayuki

doi:10.1126/science.1065757

Cited by 231 publications

(114 citation statements)

References 41 publications

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“…4) for prostate cancer that include five different carbohydrate antigens: Globo-H, STn, Tn, TF, and Le y . We hoped to evaluate as potential immuno carriers, the protein keyhole limpet hemocyanin (KLH) (28) 3 Cys) (29). Although KLH, a molluscan protein, has been used extensively in many vaccines and provides for a favorable immune response (30), the Pam 3 Cys lipid, a known potent B cell stimulant, has only been minimally evaluated in preclinical and clinical settings (15,31).…”

Section: Carbohydrate-based Cancer Vaccinesmentioning

confidence: 99%

Prospects for total synthesis: A vision for a totally synthetic vaccine targeting epithelial tumors

Keding

2004

Proc. Natl. Acad. Sci. U.S.A.

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Section: Carbohydrate-based Cancer Vaccinesmentioning

confidence: 99%

Prospects for total synthesis: A vision for a totally synthetic vaccine targeting epithelial tumors

Keding

2004

Proc. Natl. Acad. Sci. U.S.A.

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“…The left-hand portions of CTX3C (CTX3C-ABCD and CTX3C-ABCDE) were synthesized according to previously described methods (22,23). CTX3C-ABCDE was conjugated to KLH to yield ABCDE-KLH for immunization of mice to prepare the 10C9 monoclonal antibody (11).…”

Section: Preparation Of Antigen Fragments Ctx3c-abcd and Ctx3c-abcde-mentioning

confidence: 99%

How Protein Recognizes Ladder-like Polycyclic Ethers

Tanaka

Tsumuraya

et al. 2008

Journal of Biological Chemistry

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Ciguatoxins are a family of marine toxins composed of transfused polycyclic ethers. It has not yet been clarified at the atomic level on the pathogenic mechanism of these toxins or the interaction between a polycyclic ether compounds and a protein.Using the crystal structures of anti-ciguatoxin antibody 10C9 Fab in ligand-free form and in complexes with ABCD-ring (CTX3C-ABCD) and ABCDE-ring (CTX3C-ABCDE) fragments of the antigen CTX3C at resolutions of 2.6, 2.4, and 2.3 Å , respectively, we elucidated the mechanism of the interaction between the polycyclic ethers and the antibody. 10C9 Fab has an extraordinarily large and deep binding pocket at the center of the variable region, where CTX3C-ABCD or CTX3C-ABCDE binds longitudinally in the pocket via hydrogen bonds and van der Waals interactions. Upon antigen-antibody complexation, 10C9 Fab adjusts to the antigen fragments by means of rotational motion in the variable region. In addition, the antigen fragment lacking the E-ring induces a large motion in the constant region. Consequently, the thermostability of 10C9 Fab is enhanced by 10°C upon complexation with CTX3C-ABCDE but not with CTX3C-ABCD. The crystal structures presented in this study also show that 10C9 Fab recoginition of CTX3C antigens requires molecular rearrangements over the entire antibody structure. These results further expand the fundamental understanding of the mechanism by which ladder-like polycyclic ethers are recognized and may be useful for the design of novel therapeutic agents by antibodies, marine toxins, or new diagnostic reagents for the detection and targeting of members of the polycyclic ether family.Ciguatoxins are a family of ladder-like polycyclic ethers that causes ciguatera seafood poisoning in tropical and subtropical regions; more than 50,000 people suffer annually from this type of food poisoning (1-7). CTX3C, which contains 13 ether rings, is probably the best known the member of polycyclic ether family. Although CTX3C is known to bind to voltage-sensitive sodium channels, like other polycyclic ether toxins (8 -10), the precise pathogenic mechanism remains to be elucidated, and methods for the treatment of ciguatera poisoning have not yet been developed (5).Oguri et al. (11) established a direct sandwich enzyme-linked immunosorbent assay using two distinct monoclonal antibodies (10C9 and 3D11) to detect CTX3C at the parts per billion level with no cross-reactivity against other related marine toxins. 10C9 IgG is prepared by immunization of mice with a carrier protein (keyhole limpet hemocyanin (KLH) 3 ) conjugated to the ABCDE-ring of CTX3C. 10C9 IgG binds not only to CTX3C-ABCDE but also to full-length CTX3C (Fig. 1), with dissociation constants of 0.8 and 2.8 nM, respectively. Because the skeletons of polycyclic ethers are so rigid and because the compounds are so large (12-15) (they extend beyond the binding surface of the paratope of the antibody (200 -400 Å 2 ) (16 -21)), how the antibody recognizes the polycyclic ethers within the limited areas of the antigen-bindin...

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“…On the other hand, oxidative treatment of 27 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) resulted in a complex mixture, presumably attributable to the low reactivity of pseudoaxial C44-benzyloxy group and competing undesired oxidation in particular involving the A ring. Conversion of 27 to 1 was realized by a carefully controlled Birch reduction; treatment of 27 with sodium in NH 3 ͞EtOH͞THF at Ϫ90°C for 10 min resulted in global deprotection to yield pure synthetic CTX3C 1 (7% yield after HPLC purification) (23).…”

Section: Resultsmentioning

confidence: 99%

“…This prompted us to start a program of chemical construction of ciguatoxins. Herein, we describe full details of the total synthesis of ciguatoxin CTX3C 1 (23)(24)(25) and subse-quent efforts that have provided an improved second-generation total synthesis.…”

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confidence: 99%

First- and second-generation total synthesis of ciguatoxin CTX3C

Inoue

Miyazaki

Uehara

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. Furthermore, the large (3 nm in length) and complex molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. In this article, the full details of studies leading to the total synthesis of ciguatoxin CTX3C are provided. The key elements of the first-generation approach include O,O-acetal formation from the right and left wing fragments, conversion from O,O-acetal to O,S-acetal, a radical reaction to cyclize the G ring, a ring-closing metathesis reaction to close the F ring, and final removal of the 2-naphtylmethyl protective groups. Subsequent studies provided a second-generation total synthesis, which is more concise and results in a higher yield. Second-generation synthesis was accomplished by using a direct method of constructing the key intermediate O,S-acetal from ␣-chlorosulfide and a secondary alcohol. These syntheses ensure a practical supply of ciguatoxin for biological applications.ciguatera ͉ polyether ͉ convergent strategy C iguatera is a human intoxication caused by the ingestion of certain reef fish (1). More than 20,000 people suffer annually from ciguatera, making it one of the most common forms of nonbacterial food poisoning. Ingestion of affected fish leads to neurological, gastrointestinal, and cardiovascular disorders, which may last up to a month or more. The most prominent symptom is a disorder of temperature sensation. Specifically, touching cold water can induce pain similar to that of an electric shock. Other symptoms include diarrhea, vomiting, muscle pain and itching, whereas paralysis, coma, and even death may occur in severe cases.Yasumoto et al. (2) identified an epiphytic dinoflagellate, Gambierdiscus toxicus, as the causative organism and demonstrated that dinoflagellate-derived toxins are transferred by the food chain to various fish. About 100 species of fish cause ciguatera, and ciguateric fish look, taste, and smell like normal uncontaminated fish. In addition, the occurrence of poisoning is completely unpredictable. Current difficulties in predicting, detecting, and treating ciguatera have had an adverse socioeconomic impact, in particular, in developing countries.Ciguatoxins are regarded as the principal causative toxins of ciguatera seafood poisoning (Fig. 1) (3, 4). In 1989, the Yasumoto group successfully elucidated the structures of ciguatoxin (CTX) (4) and CTX4B (3) (5, 6), which were found to be large polycyclic ethers having molecular lengths Ͼ3 nm. They subsequently isolated other congeners including CTX3C (1) (7) and 51-hydroxyCTX3C (2) (8). To date, the structures of Ͼ20 congeners of ciguatoxins have been determined (9, 10).The lethal potencies of ciguatoxins (LD 50 ϭ 0.25-4 g͞kg) by i.p. injection into mic...

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Total Synthesis of Ciguatoxin CTX3C

Cited by 231 publications

References 41 publications

Prospects for total synthesis: A vision for a totally synthetic vaccine targeting epithelial tumors

Prospects for total synthesis: A vision for a totally synthetic vaccine targeting epithelial tumors

How Protein Recognizes Ladder-like Polycyclic Ethers

First- and second-generation total synthesis of ciguatoxin CTX3C

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