Synthesis and Biological Evaluation of Water Soluble Taxoids Bearing Sugar Moieties

Mandai, Tadakatsu; Okumoto, Hiroshi; Oshitari, Tetsuta; Nakanishi, Kenji; Mikuni, Katsuhiko; Hara, Koji; Hara, Kozo; Iwatani, Wakao; Amano, Tetsuya; Nakamura, Kae; Tsuchiya, Yoshihiro

doi:10.3987/com-00-s(i)34

Cited by 39 publications

(34 citation statements)

References 3 publications

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“…Compounds 6a-d showed almost equal in vitro antitumor activity to 2, although 6e did not, whereas compounds 5a-d exhibited lower antitumor activity than 1. 15) Furthermore, as indicated in the present experiments, 6a, 6c and 6d were found to show higher in vivo antitumor activity than 1 with constant dose (20 mg/kg/d). The therapeutic efficacy of 6c was equivalent to that of 2, which is superior to that of 1.…”

Section: Discussionmentioning

confidence: 52%

“…In Vivo Antitumor Activity against P388 Leukemia Cells In a previous paper, 15) we reported that in vitro antitumor activity of paclitaxel derivatives (5a-d) was inferior to that of 1. However, in vitro antitumor activity of docetaxel derivatives (6a-e) proved to be comparable to 2, with the exception of 6e.…”

Section: Resultsmentioning

confidence: 99%

“…However, in vitro antitumor activity of docetaxel derivatives (6a-e) proved to be comparable to 2, with the exception of 6e. 15) These findings encouraged us to evaluate in vivo antitumor activities against P388 leukemia cells. We then selected 4 compounds: 6a; 6c; 6d; and 6e.…”

Section: Resultsmentioning

confidence: 99%

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In Vivo Antitumor Activity of Novel Water-Soluble Taxoids

Mikuni

Nakanishi

Hara

et al. 2008

Biological & Pharmaceutical Bulletin

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Paclitaxel (1, Taxol ® ), a diterpenoid originally isolated from the bark of the Pacific yew, Taxus brebiforia, is a powerful inhibitor of microtubule assembly in tumor cells and is currently used in the treatment of various kinds of cancers. 1)However, poor water solubility (0.4 mg/ml) compromises its use as an anticancer agent. Cremophor EL ® (polyoxyethylated castor oil) was therefore designed as a solubilizing agent to enhance water solubility (60 mg/ml), but causes hypersensitivity in patients. Conversely, docetaxel (2, Taxotere ® ), an analogue of paclitaxel exerting powerful antitumor activity, is more soluble (14 mg/ml) than paclitaxel, but solubility is not greatly improved.To date, much effort has been devoted to the synthesis of paclitaxel analogues with reduced side effects and improved solubility. For instance, a number of taxoids bound to hydrophilic functionalities such as polyethylene glycols, [2][3][4] amino acids, 5) phosphates, 6-8) malic acid 9) and sugars 10,11) have been identified as prodrugs of 1. Interestingly, a naturally occurring glycoside-bound paclitaxel (7-O-xylosylpaclitaxel, 3 12,13) ) reportedly shows potent activity in the disassembly of microtubules, which prompted us to export new sugar-bound taxoids.At an earlier stage of our project, efforts were made to synthesize sugar-bound taxoids enzymatically. However, the attempted glycosylation with a variety of enzymes failed entirely, probably due to both the intrinsically poor water-solubility and reactivity of 1. Accordingly, we turned our attention to the chemical synthesis of sugar-bound taxoids. Two problematic issues exist in the glycosylation of 7-OH of 1. One is the poor solubility of 1 in organic solvent, and the other is the inevitable use of a Lewis acid to activate anomeric functionalities of sugars. We were thus concerned that the baccatin nucleus would be damaged if conventional glycosylation protocols were adopted. In this context, we designed glycosyloxy acetic acid ( 4 14) ) and achieved esterification of 4 to 7-OH of 1.We have recently reported on the water-solubility and in vitro antitumor activity of taxoids 5a-d and 6a-e, which are esterified with 4 at either 7-OH of 1 or 10-OH of 2.15) We report herein in vivo antitumor activity of these new taxoids. (Fig. 3, 5a-d, 6a-e) was synthesized as described previously. MATERIALS AND METHODS Chemicals and Agents Each taxoid15) The quantity of those taxoids was analyzed by high-performance liquid chromatography (HPLC) on a C18 column (Taxil 5 mm, 250ϫ4.6 mm I.D.; MetaChem Technologies, Torrance, CA, U.S.A.) using methanol/waterϭ65/35 as eluent with a flow rate of 0.5 ml/min at 35°C. Taxoids were detected by absorption at 230 nm using an SPV-10A photodiode array detector (Shimadzu, Kyoto, Japan). Human serum AB type was purchased from Dainippon Pharmaceutical (Osaka, Japan). Rat serum was prepared from Sprague Dawley rats (Nippon Ensuiko Sugar Refining Co., Ltd.; Japan: b Kaken Pharmaceutical Co., Ltd.; Shinomiya, Japan: and c Department of Life Science, Kurashik...

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Section: Discussionmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

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In Vivo Antitumor Activity of Novel Water-Soluble Taxoids

Mikuni

Nakanishi

Hara

et al. 2008

Biological & Pharmaceutical Bulletin

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“…As the water solubility of paclitaxel is very low (0.00025 mg/ml) [267], many prodrug designs were focused on improving its water solubility to avoid the use of detergents. Thus, the C-2 0 position was substituted with variety of carboxylic esters [268,269], phosphate esters [270], amino acids [271], sugars [272], and other hydrophilic groups [273]. One interesting example of a water-soluble prodrug is presented in Scheme 6.22 [267,[274][275][276].…”

Section: Paclitaxel and Its Derivativesmentioning

confidence: 99%

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

Ziora

Skwarczynski

Kiso

2011

Amino Acids, Peptides and Proteins in Organic Chemistry

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“…Several complementary strategies, including semisynthesis, pathway engineering, and in vitro enzymatic glycosylation techniques, have emerged from recent research as effective means of altering the natural product sugar structures (6,8,9,11,17,32). A well-known example of the improvement in water solubility is the discovery of naturally occurring glycosides such as 7␤-xylosyl-10 deacetyl paclitaxel, a taxane glycocojugate (20). This analog was also more than 2 orders of magnitude more water soluble than the original paclitaxel.…”

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confidence: 99%

Enzymatic Glycosylation of Nonbenzoquinone Geldanamycin Analogs via Bacillus UDP-Glycosyltransferase

Jang

Woo

et al. 2012

Appl Environ Microbiol

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c Geldanamycin (GM) is a naturally occurring anticancer agent isolated from several strains of Streptomyces hygroscopicus. However, its potential clinical utility is compromised by its severe toxicity and poor water solubility. For this reason, considerable efforts are under way to make new derivatives that have both good clinical efficacy and high water solubility. On the other hand, glycosylation is often a step that improves the water solubility and/or biological activity in many natural products of biosynthesis. Here, we report the facile production of glucose-conjugated nonbenzoquinone GM analogs using the Bacillus UDP-glycosyltransferase BL-C. Five aglycon substrates containing nonbenzoquinone aromatic rings were chosen to validate the in vitro glycosylation reaction. Putative glucoside compounds were determined through the presence of a product peak(s) and were also verified using LC/MS analyses. Further, the chemical structures of new glucoside compounds 6 and 7 were elucidated using spectroscopy data. These glucoside compounds showed a dramatic improvement in water solubility compared with that of the original aglycon, nonbenzoquinone GM.

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Synthesis and Biological Evaluation of Water Soluble Taxoids Bearing Sugar Moieties

Cited by 39 publications

References 3 publications

In Vivo Antitumor Activity of Novel Water-Soluble Taxoids

In Vivo Antitumor Activity of Novel Water-Soluble Taxoids

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

Enzymatic Glycosylation of Nonbenzoquinone Geldanamycin Analogs via Bacillus UDP-Glycosyltransferase

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