Syntheses and antitumor activities of 7-O-(2,6-dideoxy-2-fluoro-.ALPHA.-L-talopyranosyl)daunomycinone and -adriamycinone.

Tsuchiya, Tsutomu; Takagi, Yasushi; Ok, Kwang-Dae; Umezawa, Sumio; Takeuchi, Tomio; Wako, Nobuko; Umezawa, Hamao

doi:10.7164/antibiotics.39.731

Cited by 22 publications

(6 citation statements)

References 9 publications

(2 reference statements)

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“…3‘-Deamino-3‘-hydroxydoxorubicin 1 , whose substituent at C-5‘ is a methyl, was reported 23 to show the highest T/C value (462%) at 25 mg/kg (P388 murine leukemia by single ip injection on the first day; no long-term survivors were reported). In the case of 2 , 60-day survivors were observed in a relatively high dose range (2.5−5 mg/kg/day) . Comparison of these results indicates that 3 has a remarkably high potency in vivo .…”

Section: Resultsmentioning

confidence: 88%

“…In the case of 2, 60-day survivors were observed in a relatively high dose range (2.5-5 mg/kg/day). 24 Comparison of these results indicates that 3 has a remarkably high potency in vivo. The higher activity of 3 versus 1 or 2 may be reasonably ascribed to the presence of a trifluoromethyl group at C-5′, whose contribution to its stability as well as high lipophilicity may enhance the cellular uptake of this analog, facilitating the transportation into organs as well.…”

Section: Resultsmentioning

confidence: 99%

“…On the 2‘-position, most of the DOX analogs including 1 have no substituent, and this will be the reason why these antibiotics are unstable in acidic conditions, giving inactive aglycons. This problem, however, was solved by introducing a strongly electron-withdrawing fluorine at C-2‘, as illustrated by 7- O -(2,6-dideoxy-2-fluoro-α- l -talopyranosyl)adriamycinone , ( 2 ), which was stable against acid and exhibited stronger antitumor activity with less toxicity in comparison to those for DOX. Additionally, 2 was found to be absorbed more rapidly and accumulated more readily into tumor cells than DOX.…”

Section: Introductionmentioning

confidence: 99%

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A 5‘-(Trifluoromethyl)anthracycline Glycoside: Synthesis of Antitumor-Active 7-O-(2,6-Dideoxy-6,6,6-trifluoro-α-l-lyxo-hexopyranosyl)adriamycinone

et al. 1996

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7-O-(2,6-Dideoxy-6,6,6-trifluoro-alpha-L-lyxo-hexopyranosyl)adriam ycinone (3), whose substituent at C-5' is a lipophilic trifluoromethyl group, has been prepared by coupling of 3,4-di-O-acetyl-2,6-dideoxy-6,6,6-trifluoro-alpha-L-lyxo-hexopyran osyl bromide (20) with 14-O-(tert-butyldimethylsilyl)adriamycinone under the Koenigs-Knorr conditions. The key step in this synthesis was the C-trifluoromethylation of 5-O-acetyl-2,3-di-O-benzyl-4-deoxy-aldehydo-L-erythro-pentose (10), derived from D-lyxose in 10 steps, with (trifluoromethyl)trimethylsilane in the presence of tetrabutylammonium fluoride, whereupon 1,1,1-trifluoro-L-arabino-hexitol (11) was obtained along with its 2-epimer. The synthetic product 3 showed remarkable antitumor activity in vivo in a low dose range compared to the analogs including doxorubicin. The fact may be ascribed to the presence of a trifluoromethyl group at C-5', suggesting the importance of the group in view of biological activity.

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Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A 5‘-(Trifluoromethyl)anthracycline Glycoside: Synthesis of Antitumor-Active 7-O-(2,6-Dideoxy-6,6,6-trifluoro-α-l-lyxo-hexopyranosyl)adriamycinone

et al. 1996

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“…In conjunction with our program directed toward exploration of novel anthracycline congeners as candidate anticancer agents, 5,10) we recently succeeded in the first total syntheses of 14-fluoroanthracyclines (5)(6)(7)(8)(9)(10) which have L-daunosamine, D-2-deoxyribose, or L-2-deoxyfucose as their glycosidic sugars,1) by employing a novel fluorination reaction and an efficient glycosidation method. This report deals with the syntheses and preliminary evaluation of the anticancer activity of 5-10.1) Results and Discussion Preparation of (+)-14-Fluoro-4-demethoxydaunomycinone (( +)-15a) and ( +)-14-Fluorodaunomycinone ((+)-15b)…”

mentioning

confidence: 99%

“…Only a low yield of (+)-14-fluoro-4-demethoxydaunomycinone ((+)-15a) was obtained when the C14-bromide prepared from 4-demethoxydaunomycinone11) was subjected to fluorination in the same manner as described for dl-12a. (7)(8)(9)(10) in which the L-daunosamine residue was replaced with D-2-deoxyribose and L-2-deoxyfucose. (19a, b-21a, b).…”

mentioning

confidence: 99%

14-Fluoroanthracyclines. Novel syntheses and antitumor activity.

Matsumoto

Ohsaki

Yamada

et al. 1988

CHEMICAL & PHARMACEUTICAL BULLETIN

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The 14-fluoroanthracyclines (5-10) carrying L-daunosamine, D-2-deoxyribose, or L-2-deoxyfucose as their glycosidic sugar moieties, were synthesized starting from (-)-7-deoxy-4-demethoxydaunomycinone ((R)-11a) or (-)-7-deoxydaunomycinone ((R)-11b). As key steps, the synthetic route features a novel fluorination reaction in which tetrabutylammonium fluoride is employed in the presence of a half equivalent of p-toluenesulfonic acid, and the previously explored glycosidation reaction in which trimethylsilyl trifluoromethanesulfonate is utilized as an activating reagent. In P388 in vitro tests, 5, 6, 9, and 10 exhibited prominent cytotoxicity comparable with that of adriamycin (1). Notable antitumor activity was also observed for 6 and 9 in P388 in vivo tests.The anthracycline antibiotics, adriamycin (1) and daunorubicin (2), are important anticancer agents which are widely used in the clinic for treating leukemia and solid tumors.2) However, their utility for cancer chemotherapy is seriously restricted by various undesirable side effects, the most well-known and serious of which is dose-related cardiotoxicity.2) Thus, extensive studies on the structure-activity relationships have been carried out to overcome these disadvantages, culminating in the syntheses of various notable congeners of 1 and 2, some of which show superior anticancer activity in the P388 in vivo murine leukemia test system.2,3) Among these congeners of 1 and 2, 4-demethoxyadriamycin (3) and 4-demethoxydaunorubicin (4) are well recognized to exhibit better therapeutic indices than natural 1 and 2.2-5)With the aims of improving the therapeutic properties of pharmacologically active compounds, and moreover, of finding novel pharmacological activities different from those of the parent compounds, a great number of fluorinated derivatives of biologically active compounds have been prepared in the last decade.6,7) In the field of anthracyclines, some derivatives involving fluorinated sugars') or D-rings9) have recently been synthesized. However, syntheses of anthracycline congeners carrying fluorinated C9-side chains have not been reported, probably due to the difficulty which may be encountered in introducing

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Cellular uptake and antitumor activity of the new anthracycline analog DA-125 in human cancer cell lines

Lim

Kim

Yang

et al. 1997

Cancer Chemotherapy and Pharmacology

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To predict the clinical usefulness of DA-125, a newly developed doxorubicin analog, we compared its antitumor activity against 20 different human cancer cell lines with that of doxorubicin using the MTT in vitro chemosensitivity test. We also measured and compared the cellular uptake of this drug and doxorubicin in two cancer cell lines and their doxorubicin-resistant sublines. In the MTT test, DA-125 showed lower IC50 values than doxorubicin for 14 of 20 cell lines. DA-125 was more potent than doxorubicin for hepatocellular cancer cells with high mdr 1 expression. Among cancer cells from the stomach and colon, DA-125 was more potent than doxorubicin in 12 of 14 cell lines. We also investigated the cross-resistance of this drug with doxorubicin using four doxorubicin-resistant cancer cell sublines. Except in one cell line, there was very low cross-resistance. Cellular drug-uptake experiments were performed for two gastric cancer cell lines and their doxorubicin-resistant sublines. In this experiment, DA-125 was found to be very rapidly and completely converted to its active metabolite, M1, in the culture media. After this conversion, M1 was incorporated into these cancer cells more rapidly and reached higher intracellular concentrations than doxorubicin, suggesting that DA-125 (as M1) could achieve earlier and higher levels of intracellular accumulation than doxorubicin in its target tissues from the bloodstream. As a possible alternative antineoplastic agent to doxorubicin, DA-125 awaits further evaluation for its antitumor activity and toxicity.

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Syntheses and antitumor activities of 7-O-(2,6-dideoxy-2-fluoro-.ALPHA.-L-talopyranosyl)daunomycinone and -adriamycinone.

Cited by 22 publications

References 9 publications

A 5‘-(Trifluoromethyl)anthracycline Glycoside: Synthesis of Antitumor-Active 7-O-(2,6-Dideoxy-6,6,6-trifluoro-α-l-lyxo-hexopyranosyl)adriamycinone

A 5‘-(Trifluoromethyl)anthracycline Glycoside: Synthesis of Antitumor-Active 7-O-(2,6-Dideoxy-6,6,6-trifluoro-α-l-lyxo-hexopyranosyl)adriamycinone

14-Fluoroanthracyclines. Novel syntheses and antitumor activity.

Cellular uptake and antitumor activity of the new anthracycline analog DA-125 in human cancer cell lines

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