XB596, a promising bis-naphthalimide anti-cancer agent

Chen, S F; Behrens, Davette L.; Behrens, Carl H.; Czerniak, Philip M.; Dexter, Daniel L.; Dusak, B L; Fredericks, Jessica; Gale, Kevin C.; Gross, Janet L.; Jiang, Jack B.; Kirshenbau, m; McRipley, Ronald J.; Papp, L. M.; Patten, Arthur D.; Perrella, Frank W.; Seitz, Steven P.; Stafford, M. P.; Sun, Jung‐Hui; Sun, Tiffany; Wuonola, Mark A.; Hoff, D. Von

doi:10.1097/00001813-199308000-00005

Cited by 20 publications

(16 citation statements)

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“…For comparison, the activity of the full‐length insect DHODH activity was found to be reduced by 20–60% on addition of these quinones as alternative electron acceptors [29]. Similar observations were described when Q 0 , vitamin K1 or menadione were tested instead of Q 10 or Q 6 with the isolated human or bovine enzyme [14,25]. These findings point to a considerable interference of the long N‐terminal mitochondrial targeting sequence of the AT‐DHODH (57 amino acids versus 19 of the insect and 10 of the human enzyme) with the side chain of the quinone.…”

Section: Resultsmentioning

confidence: 64%

“…Rather, the metabolic inhibitors 5‐fluorouracil, 5‐fluoroorotic acid and N ‐phosphonoacetyl‐ L ‐asparate, which are toxic to plant cells just as to animal cells [5,6], have been used as tools to understand the regulation and expression of pyrimidine biosynthesis in plants. Because specific inhibitors for DHODH of these organisms have not been described, we investigated the recombinant plant enzyme for its susceptibility to two compounds already proven as potent inhibitors of the mammalian DHODH in the nanomolar range: brequinar, originally developed as cytostatic agent [14] and A77‐1726 with anti‐inflammatory efficacy profile [12]. The present study revealed only a marginal inhibitory effect on A. thaliana DHODH: in the presence of 100 μM A77‐1726, the activity of the full‐length DHODH was reduced only by 10%, that of the truncated one was reduced by 25%.…”

Section: Resultsmentioning

confidence: 99%

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Plant dihydroorotate dehydrogenase differs significantly in substrate specificity and inhibition from the animal enzymes

et al. 2002

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The mitochondrial membrane bound dihydroorotate dehydrogenase (DHODH; EC 1.3.99.11) catalyzes the fourth step of pyrimidine biosynthesis. By the present correction of a known cDNA sequence for Arabidopsis thaliana DHODH we revealed the importance of the very C-terminal part for its catalytic activity and the reason why^in contrast to mammalian and insect species^the recombinant plant £avoenzyme was unaccessible to date for in vitro characterization. Structure^activity relationship studies explained that potent inhibitors of animal DHODH do not signi¢cantly a¡ect the plant enzyme. These difference could be exploited for a novel approach to herb or pest growth control by limitation of pyrimidine nucleotide pools.

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Section: Resultsmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Plant dihydroorotate dehydrogenase differs significantly in substrate specificity and inhibition from the animal enzymes

et al. 2002

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“…In view of these interesting results, Braña et al in 1995 synthesized a series of 5-amino-8-nitronaphthalimides to combine the electron withdrawing effects of the nitro group and the electron donating aspects of the amino group [6]. These compounds (59)(60)(61)(62)(63)(64)(65) were tested for their in vitro cytotoxicity against human CX-1 colon and LX-1 lung carcinomas ( Table 3) and showed higher activity than amonafide and mitonafide [3]. Two of them also showed promising in vivo activity in the L1210 leukemia and Fig.…”

Section: Monomeric Naphthalimides: Design Synthesis Cytotoxic Activmentioning

confidence: 99%

“…XB596 (methanesulfonate salt of 93), a representative of a bis-naphthalimide series synthesised by Chen et al [65] has been found to be a DNA intercalator, binding to DNA with guanine-cytosine sequence selectivity, inducing DNA singlestrand breaks but not double-strand breaks in treated L1210 cells. Li et al [9] have additionally shown that the presence of a thiazole ring fused to the naphthalimide skeleton leads to greater cytotoxic potency with respect to the "non-fused" compound amonafide.…”

Section: Other Mechanismsmentioning

confidence: 99%

Naphthalimides and Azonafides as Promising Anti-Cancer Agents

Ingrassia¹,

Lefranc²,

Kiss³

et al. 2009

CMC

133

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Naphthalimides, a class of compounds which bind to DNA by intercalation, have shown high anti-cancer activity against a variety of murine and more notably human cancer cell lines. Azonafide derivatives are also potential anti-tumor agents which are structurally related to the naphthalimides. Derivatives of azonafide have shown enhanced activity against various cancer models, especially leukemias, breast cancer and melanoma. Naphthalimides in general and amonafide in particular, are most probably the agents which have been involved in the greatest number of clinical trials without ever acceding to the market because of dose-limiting toxicity. This statement also reflects the immense interest that oncologists have paid to this class of compounds with respect to their anti-cancer potential. While the first generation of naphthalimides were mainly topoisomerse II poisons, some new compounds display novel mechanism of action. In contrast to the most widely used topo II poisons, including etoposide, adriamycin and their analogues, which often induce multi-drug resistance, several naphthalimide-related compounds have been reported not to be affected by this phenomenon. Multi-disciplinary approaches including medicinal chemistry, early toxicology and DMPK, in vivo activity assessment in diverse preclinical models and in-depth mechanism of action deciphering, along with the lessons learnt from previous and currently ongoing clinical trials, have resulted in the generation of a number of novel promising naphthalimide derivatives. It is thus reasonable to expect that members of this class of compounds will reach the oncology market in the near future.

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“…Investigators at Du Pont Merck (Wilmington, DE) have synthesized another series of bisnaphthalimides [50]. The compounds showed an in vitro and in vivo spectrum of activity similar to the bisnaphthalimides described above [51][52][53][54][55].…”

Section: Other Bisnaphthalimidesmentioning

confidence: 99%

Naphthalimides as Anticancer Agents: Synthesis and Biological Activity

Braña

Ramos

2001

CMCACA

254

168

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Naphthalimides are a class of compounds with high antitumor activity upon a variety of murine and human tumor cells. These compounds bind to DNA by intercalation of the chromophore and two of them, mitonafide and amonafide, were used in clinical trials. The therapeutic properties of these lead drugs were improved by designing bisintercalating agents. One of these, elinafide, showed intense in vitro and in vivo activity and is currently being used in clinical trials against solid tumors. In this paper, the history of elinafide is described.

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XB596, a promising bis-naphthalimide anti-cancer agent

Cited by 20 publications

References 0 publications

Plant dihydroorotate dehydrogenase differs significantly in substrate specificity and inhibition from the animal enzymes

Plant dihydroorotate dehydrogenase differs significantly in substrate specificity and inhibition from the animal enzymes

Naphthalimides and Azonafides as Promising Anti-Cancer Agents

Naphthalimides as Anticancer Agents: Synthesis and Biological Activity

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