Synthesis and preliminary antitumor activity evaluation of a DHA and doxorubicin conjugate

Wang, Yuqiang; Li, Lianfa; Jiang, Wei; Yang, Zhaoqi; Zhang, Zaijun

doi:10.1016/j.bmcl.2006.02.066

Cited by 52 publications

(53 citation statements)

References 14 publications

(6 reference statements)

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“…However, most of the prodrug conjugates show modifications at 3 ¶ amino of the hexopyranosyl ring in DOX by aminolysis (28)(29)(30). Other than aminolysis reactions, acetyl group at C8 in DOX.HCl was conjugated with cis-4,7,10,13,16,19-docosahexenoic acid to form a hydrazone bond (31). The objective previously described in the literature was to selectively cleave the hydrazone bond to release DOX.HCl in the tumor cells, leading to selective toxicity.…”

Section: Discussionmentioning

confidence: 98%

Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

et al. 2007

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Section: Discussionmentioning

confidence: 98%

Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

et al. 2007

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“…Furthermore, one can imagine to associate doxorubicin with one of w-3 polyunsaturated fatty acids known to enhance the chemosensitivity of cancer cells in vitro. 24,25) …”

Section: Discussionmentioning

confidence: 99%

On the Interaction of Doxorubicin with Oleate Ions: Fluorescence Spectroscopy and Liquid-Liquid Extraction Study

Munnier

Tewes

Cohen-Jonathan

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Doxorubicin (DOX) is an antineoplastic agent of the anthracycline family used as a first-line treatment in numerous neoplastic diseases, particularly in breast cancer.1) The progression of tumor cell resistance, in particular multidrug resistance (MDR), is one of the main factors which limit its employment.2) MDR is generally associated with a decreased intracellular accumulation of drug related to a membrane glycoprotein, the P-gp that contributes to a rapid expelling of the drug from the cell.3) An interesting way to overcome this active efflux would be to support the drug accumulation into the cell, in particular by increasing its capacity to cross lipidic membranes. One can act upon the membrane fluidity or act upon the hydrophilic/lipophilic properties of the drug.DOX molecule (see structure on Fig. 1) is considered hydrophilic at physiological pH because it presents a positive charge on the sugar moiety. The more lipophilic molecular form of DOX is dominant at moderately alkaline pHs, between 8.2 and 9.5, the pK a values of the amine and the phenol in position 11 respectively.4) The hydrophilicity of DOX is also depending on the drug concentration, since beyond a concentration of 30 mM DOX molecules are prone to form less hydrophilic dimmers (stacking effect) which precipitate in aqueous solution. The increase of the pH, i.e. of the neutral form percentage, is in favor of the stacking phenomenon. 5,6) It has been recently shown that lipophilicity of cationic drugs 7,8) can be increased by association with an anion, namely with a long chain ion of a fatty acid.9,10) Nevertheless, no study is devoted to the molecular interaction between the drug and the ion. On the other hand, combined use of an anticancer drug, paclitaxel, with different fatty acids, has been shown to enhance mortality of cancer cells in vitro.11) It has not yet been established whether this gain in efficacy is dependent on an assembly between the drug and the fatty acid ion.Association DOX-fatty acid could be more lipophilic than DOX alone, and enter more efficiently into the cell. It could also facilitate drug encapsulation into pharmaceutical formulations based on hydrophobic polymers or liposomes. 7,9) Oleic acid is a good candidate for such an association within a feasibility study: it is the simplest of the w-9 fatty acid family (Fig. 1), and possesses a long hydrophobic chain that could contribute to a gain of lipophilicity of the association. Moreover, oleates are non-toxic and the behavior of oleic acid and its ion (oleate, OA Ϫ ) in aqueous solution is rather well studied. [12][13][14][15] Fluorescence spectroscopy has been successfully used to study interactions between DOX and its surrounding, for instance when the drug intercalates DNA 16,17) or penetrates within membrane models or liposomal drug carriers. 18,19) Indeed, the dihydroanthraquinone moiety of DOX is a well known fluorophore excitable with visible light (absorption maxima at 480-500 nm). Fluorescence spectroscopy Increase of lipophilicity of cationic doxorubicin (DO...

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“…At the difference with ester or amide linkages between the phenolic compound and the PUFA part, non hydrolysable bounds have been obtained [38] [18][19]29] (dopamine and analogues) 11 [26,29,67] (vanillyl amine) 14 [17] ( [28] (Farinosone C analogue) 21 [20] (juglone) 22 [23] (shikonin) Dox-hyd-PUFA: 24a Dox-3-ami-PUFA: 24b (doxorubicin) [25,[63][64][65] 23 [27] (podophyllotoxin analogue) DDPT 15 [37] (phloroglucinol) 4'-PUFA:17a [22,37] 3-DHA: 17b (resveratrol) 18 [21] (trimethoxy anilide) 19 [24,66] (diisopropylphenol) 3 5 4' 3 3 2 [34][35] (EGC) 3 [36] (quercetin) 4 [15] (naringin) 5 [10][11][13][14][15] (rutin) 6 [12] (phloridzin) 7 [12] (isoquercitrin) 8 [38] 9 [30] 10 [ linker [39]. Since pH in tumor cells is lower than in healthy tissue, the hydrazone bond, stable at pH 7.4, is rapidly cleaved at lower pH in cancerous cells.…”

Section: Chemical Synthesismentioning

confidence: 99%

Omega-3 polyunsaturated lipophenols, how and why?

et al. 2016

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Polyphenols and n-3 polyunsaturated fatty acids (PUFAs) are two classes of natural compounds, which have been highlighted in epidemiological studies for their health benefits. The biological activities of those two families of metabolites on oxidation, inflammation, cancer, cardiovascular and degenerative diseases have been reported in vitro and in vivo. On the other hand, chemical bonding between the two structures leading to n-3 lipophenol derivatives (or phenolipids) has been studied in numerous works over the last decade, and some examples could also be found from natural sources. Interest in lipophilization of phenolic structures is various and depends on the domain of interest: in food industry, the development of lipidic antioxidants could be performed to protect lipidic food matrix from oxidation. Whereas, on pharmaceutical purpose, increasing the lipophilicity of polar phenolic drugs could be performed to improve their pharmacological profile. Moreover, combining both therapeutic aspects of n-3 PUFAs and of polyphenols in a single lipophenolic molecule could also be envisaged. An overview of the synthesis and of the natural sources of n-3 lipophenols is presented here, in addition to their biological activities which point out in several cases the benefit of the conjugated derivatives.

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Synthesis and preliminary antitumor activity evaluation of a DHA and doxorubicin conjugate

Cited by 52 publications

References 14 publications

Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

On the Interaction of Doxorubicin with Oleate Ions: Fluorescence Spectroscopy and Liquid-Liquid Extraction Study

Omega-3 polyunsaturated lipophenols, how and why?

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