Total Synthesis of Nominal Diazonamides-Part 2: On the True Structure and Origin of Natural Isolates

Li, Jing; Burgett, Anthony W. G.; Esser, Lothar; Amezcua, Carlos A.; Harran, Patrick G.

doi:10.1002/1521-3773(20011217)40:24<4770::aid-anie4770>3.0.co;2-t

Cited by 183 publications

(104 citation statements)

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“…A good example of this problem is the structure determination of a multi-ring anticancer marine natural product (Lindquist et al, 1991). It was shown recently by Li, Burgett et al (2001) that one of the oxygen atoms in one of the ®ve-membered rings should have been identi®ed as NÐH. Obviously, such a misassignment has serious consequences when one attempts to synthesize such a compound from scratch (Li, Jeong et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Single-crystal structure validation with the programPLATON

2003

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The results of a single-crystal structure determination when in CIF format can now be validated routinely by automatic procedures. In this way, many errors in published papers can be avoided. The validation software generates a set of ALERTS detailing issues to be addressed by the experimenter, author, referee and publication journal. Validation was pioneered by the IUCr journalActa Crystallographica Section Cand is currently standard procedure for structures submitted for publication in all IUCr journals. The implementation of validation procedures by other journals is in progress. This paper describes the concepts of validation and the classes of checks that are carried out by the programPLATONas part of the IUCrcheckCIFfacility.PLATONvalidation can be run at any stage of the structure refinement, independent of the structure determination package used, and is recommended for use as a routine tool during or at least at the completion of every structure determination. Two examples are discussed where proper validation procedures could have avoided the publication of incorrect structures that had serious consequences for the chemistry involved.

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Section: Discussionmentioning

confidence: 99%

Single-crystal structure validation with the programPLATON

2003

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“…1C). As reported previously, growth arrest results from aberrant mitotic spindle formations (5,8). In the presence of 30 nM diazonamide A, HeLa cells assemble both mono-and multipolar spindle structures ( Fig.…”

Section: Impact Of Diazonamide a On Spindle Assembly In Hela Cells Andmentioning

confidence: 99%

“…We were able to revise that proposal through chemical synthesis (7,8). These efforts also provided access to analogs and tagged derivatives.…”

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confidence: 99%

Diazonamide toxins reveal an unexpected function for ornithine δ-amino transferase in mitotic cell division

Wang

Shang

Burgett

et al. 2007

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

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119

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We have studied a naturally occurring small-molecule antimitotic called diazonamide A. Diazonamide A is highly effective at blocking spindle assembly in mammalian cell culture and does so through a unique mechanism. A biotinylated form of diazonamide A affinity purifies ornithine ␦-amino transferase (OAT), a mitochondrial enzyme, from HeLa cell and Xenopus egg extracts. In the latter system, the interaction between diazonamide A and OAT is regulated by RanGTP. We find that specific OAT knockdown in human cervical carcinoma and osteosarcoma cells by RNA interference blocks cell division and causes cell death, the effects largely phenocopying diazonamide A treatment in these cell lines. Our experiments reveal an unanticipated, paradoxical role for OAT in mitotic cell division and identify the protein as a target for chemotherapeutic drug development.A variety of small molecules block progression through M phase of the cell cycle. The most common are tubulin ligands. Tubulin-binding toxins have helped elucidate the structure and organization of the mitotic spindle, and certain of these toxins are clinically effective as cancer chemotherapy. However, systemic disruption of the tubulin cytoskeleton has drawbacks. Microtubule poisons disturb nonmitotic functions of the cytoskeleton in both replicating cells and differentiated nondividing cells. Wasting, neutropenia, and peripheral neuropathy are severe dose-limiting toxicities common to this family of drugs in vivo (1). As a result, considerable effort has been made to identify alternative antineoplastics that target mitotic regulatory factors or components of the spindle other than tubulin (2). The development of specific inhibitors of the aurora kinases (3) and the kinesin motor protein Eg5 (2) are notable recent examples.

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“…Evaluation of the compound by the Developmental Therapeutics Program at the National Cancer Institute, including analysis by the COMPARE algorithm of the resulting differential cytotoxicity pattern (14,15), indicated diazonamide A might represent a tubulin-active agent, because its correlation coefficients of toxicity most closely paralleled antitubulin drugs (vinblastine, maytansine, paclitaxel, and vincristine). Cells treated with diazonamide A arrest at the G 2 /M boundary and fail to form appropriately organized bipolar mitotic spindles (15,16). Notably, however, studies by CruzMonserrate et al (15) indicated that diazonamide A does not compete with vinblastine or colchicine for tubulin binding.…”

mentioning

confidence: 99%

“…Earlier, we developed a successful laboratory synthesis of diazonamide A and identified its correct chemical structure (16,18). Such efforts further enabled the preparation of derivatized forms of diazonamide A useful for biochemical studies of its mode of action.…”

mentioning

confidence: 99%