Synthesis and biological evaluation of novel conjugates of podophyllotoxin and 5-FU as antineoplastic agents

Chen, Shi‐Wu; Xiang, Rong; Liu, Jian; Tian, Xuan

doi:10.1016/j.bmc.2009.03.009

Cited by 31 publications

(16 citation statements)

References 33 publications

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“…The cytotoxicity data (IC 50 ; μM) of the two different series of podophyllotoxin analogues such as 4 -[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxins (10) and conjugates of podophyllotoxin and 5-FU (11) against four different cancer cell lines was considered for the QSAR analysis [17,18]. The cytotoxicity data (IC 50 ; μM) of compound series (10 and 11) was converted into log 1/IC 50 (molar concentration) and listed in Tables 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

“…In a very recent work, Chen et al [18] reported the synthesis of a series of conjugates of podophyllotoxin together with 5-FU (11), in which the main chemical differences are the length of the side chain (where, Y = CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2 ), and the difference of amino acids. They also evaluated their cytotoxicity in in-vitro against four different human cancer cell lines.…”

Section: Qsars For the In-vitro Cytotoxicities Of The Conjugates Of Pmentioning

confidence: 99%

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A QSAR Study on the Cytotoxicity of Podophyllotoxin Analogues Against Various Cancer Cell Lines

Verma¹,

Hansch²

2010

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The powerful inhibitory activity of podophyllotoxin (a natural product) on cell growth led to the development of clinically useful anticancer agents such as etoposide, teniposide, and etopophos. Although, these podophyllotoxin derivatives show good clinical effects against various cancers, its use often results in various undesired side effects, drug resistance, and cytotoxicity towards the normal cells. In order to overcome these limitations, it is essential to search new podophyllotoxin analogues with improved anticancer activity and fewer side effects to gain the maximum benefits for the cancer patients. With this purpose, the cytotoxicity data of two series of podophyllotoxin derivatives against four different cancer cell lines was used to develop 4 QSAR models. Hydrophobic property of the molecules was found one of the most important determining factors for their activity. The developed QSAR models showed a good correlative and predictive abilities having r(2) = 0.960 to 0.836 and q(2) = 0.911 to 0.705. On the basis of QSAR 1, two compounds (10-10 and 10-11) are suggested as potential synthetic targets. Statistical diagnostics and internal validation (cross validation and Y-randomization) tests have validated all the QSAR models. These QSAR models could be useful in the rational design of potential drug molecules with an enhanced inhibitory potency.

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Section: Methodsmentioning

confidence: 99%

Section: Qsars For the In-vitro Cytotoxicities Of The Conjugates Of Pmentioning

confidence: 99%

A QSAR Study on the Cytotoxicity of Podophyllotoxin Analogues Against Various Cancer Cell Lines

Verma¹,

Hansch²

2010

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“…For example, thiocolchicine-podophyllotoxin conjugates were reported to have improved solubility and anticancer activity [15]. In addition, a series of conjugates of podophyllotoxin with 5-fluorouracil (5-FU) were reported to have better cytotoxic activity than VP-16 [16]. Structure-activity relationship (SAR) studies [17] have demonstrated that C-4 is the molecular area tolerable to significant structural diversification.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings

Xu²,

et al. 2013

Molecules

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A series of 4β-triazole-linked glucose podophyllotoxin conjugates have been designed and synthesized by employing a click chemistry approach. All the compounds were evaluated for their anticancer activity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays. Most of these triazole derivatives have good anticancer activity. Among them, compound 35 showed the highest potency against all five cancer cell lines tested, with IC 50 values ranging from 0.59 to 2.90 μM, which is significantly more active than the drug etoposide currently in clinical use. Structure-activity relationship analysis reveals that the acyl substitution on the glucose residue, the length of oligoethylene glycol linker, and the 4'-demethylation of podophyllotoxin scaffold can significantly affect the potency of the anticancer activity. Most notably, derivatives with a perbutyrylated glucose residue show much higher activity than their counterparts with either a free glucose or a peracetylated glucose residue.

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“…15,16 In light of the combined use of camptothecin (CPT) and 5-FU in clinical therapy, the conjugation of 5-FU and CPT with dipeptides improved tumor selectivity, efficiency, safety, and were comparable or superior to irinotecan. 17 Other hybrids, incorporating various pharmacophores with antitumor activity including cytarabine-5-FU, 18 cisplatin-5-FU, 19 podophyllotoxin-5-FU, 20 ampelopsin-5-FU, 21 inhanced 5-FU's physical and chemical profiles and overcame its disadvantages. With these exciting results achieved so far, 5-FU was an attractive lead compound for the development of novel antitumor agents, but few modifications were found at O 2 or O 4 positions.…”

Section: 4mentioning

confidence: 99%

Novel 5-Fluorouracil Derivatives: Synthesis and Cytotoxic Activity of 2-Butoxy-4-Substituted 5-Fluoropyrimidines

Sun¹,

Zhang²,

Li³

et al. 2013

Bulletin of the Korean Chemical Society

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Twenty two new 5-fluorouracil (5-FU) derivatives, 2-butoxy-4-substituted 5-fluoropyrimidines, were synthesized and characterized by IR, 1 H NMR, MS, HRMS. All compounds were preliminarily evaluated by MTT assay on human liver BEL-7402 cancer cell line in vitro. Ten compounds were selected to test their cytotoxic activity against A549, HL-60 and MCF-7 cancer cell lines in vitro. These compounds were more sensitive to BEL-7402 than other cell lines, particularly, cytotoxic activity of compounds 6b, 6d-f, 6p, 6s-u were in sub-micromolar scale. The highest cytotoxic potency against A549, HL-60 and MCF-7 was shown by 2-butoxy-4-chloro-5-fluoropyrimidine (5) with IC 50 values of 0.10, 1.66 and 0.59 µM, respectively. Compounds 6d and 6e were effective against MCF-7 with IC 50 9.73 µM and HL-60 with IC 50 8.83 µM, respectively.

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Synthesis and biological evaluation of novel conjugates of podophyllotoxin and 5-FU as antineoplastic agents

Cited by 31 publications

References 33 publications

A QSAR Study on the Cytotoxicity of Podophyllotoxin Analogues Against Various Cancer Cell Lines

A QSAR Study on the Cytotoxicity of Podophyllotoxin Analogues Against Various Cancer Cell Lines

Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings

Novel 5-Fluorouracil Derivatives: Synthesis and Cytotoxic Activity of 2-Butoxy-4-Substituted 5-Fluoropyrimidines

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