Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4β-amino-4′-O-demethylepipodophyllotoxin conjugates

Chang, Jang Yang; Guo, Xin; Chen, Hong Xing; Jiang, Zaoli; Fu, Qin; Wang, Hui Kang; Bastow, Kenneth F.; Zhu, Xiao Kang; Guan, Jian; Lee, Kuo Hsiung̀; Cheng, Yung Chi

doi:10.1016/s0006-2952(99)00363-9

Cited by 28 publications

(15 citation statements)

References 28 publications

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“…Lee and coworkers [140,141] employed the conjugation method to VP-16 to overcome drug resistance or to enhance the cytotoxic activity. They substituted the glycosidic moiety at C(4) with camptothecin, a topo I inhibitor, or taxol derivatives, or microtubule assembly promoters, through aromatic bridges (Fig.…”

Section: Conjugates With Other Drugsmentioning

confidence: 99%

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Podophyllotoxin Derivatives: Current Synthetic Approaches for New Anticancer Agents

You¹

2005

CPD

188

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Podophyllotoxin is an antimitotic natural product. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the water-soluble prodrug, etoposide phosphate. The cytotoxic mechanism of these drugs is the inhibition of topoisomerase II, unlike the lead compound which inhibits mitosis. Through extensive structure-activity relationship studies, several potential drug candidates were synthesized such as GL-331, TOP 53, NK611, and azatoxin. Recently, more complex and diverse analogues have been synthesized either to get more potent compounds or to overcome drug resistance. At the same time, a number of prodrug approaches have been tried to enhance the tumor selectivity or to increase the aqueous solubility. The prodrugs can release cytotoxic etoposide through the actions of hydrolysis, enzymes or catalytic antibodies. More sophisticated prodrug strategies have been applied in etoposide and these produced some interesting results. In this review, the current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.

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Section: Conjugates With Other Drugsmentioning

confidence: 99%

“…Esters with acetic to octanoic acid (138)(139)(140)(141)(142)(143) were more active than DDPT, while esters of longer alkanoic acids than hexadecanoic acid (147)(148)(149)(150) showed weaker activity. In animal tests, all of the compounds except 148, 150 showed better antitumor activity than the parent DDPT.…”

Section: Esters Carbonates and Carbamates Of Ddptmentioning

confidence: 99%

Podophyllotoxin Derivatives: Current Synthetic Approaches for New Anticancer Agents

You¹

2005

CPD

188

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“…Recently, DMEP becomes more and more commercially important as raw material for the semi-synthesis of anticancer drugs because of its structure similarity to Etoposide, which is one of the most prescribed anticancer drugs [16][17][18][19][20]. Numerous structural modifications of DMEP have been carried out in order to obtain derivatives which have been demonstrated to significant activity and high solubility [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

A novel biotransformation process of 4′-demethylepipodophyllotoxin to 4′-demethylepipodophyllic acid by Bacillus fusiformis CICC 20463, Part II: process optimization

Tang

Zhong

2009

Bioprocess Biosyst Eng

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This work optimized the novel biotransformation process of 4'-demethylepipodophyllotoxin (DMEP) into 4'-demethylepipodophyllic acid (DMEPA) by Bacillus fusiformis CICC 20463. Firstly, the biotransformation process was significantly affected by medium composition. 5 g/L of yeast extract and 10 g/L of peptone were optimal for DMEPA production (i.e., 2.81 + or - 0.21 mg/L), while not beneficial for the cell growth of B. fusiformis. This indicated that the biosynthesis of DMEPA was not corresponded well to the cell growth of B. fusiformis. 40 g/L of sucrose was optimal for DMEPA production (i.e., 2.94 + or - 0.17 mg/L), and 3 g/L of NaCl was the best for DMEPA production (i.e., 4.10 + or - 0.18 mg/L). Secondly, the production of DMEPA was significantly enhanced by the control of substrate concentration and culture pH. 100 mg/L of substrate was optimal for DMEPA production (i.e., 6.47 + or - 0.35 mg/L), and DMEPA concentration was enhanced to 38.78 mg/L by controlling culture pH at 9.0 in the stirred-tank bioreactors. The fundamental information obtained in this study provides a simple and efficient way to produce DMEPA by biotransformation.

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“…21,22 Both compounds inhibited topo I, but only 2 was active against topo II, although at a higher concentration (100 µM). Both compounds induced PLDB in KB cells and had similar in vitro cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

“…Two conjugates ( 1 and 2 ) in which the topo I inhibitor camptothecin and the topo II inhibitor 4β-anilino-4′-O-demethylepipodophyllotoxin were linked via a covalent imine bond were synthesized and evaluated for biochemical and biological activities. 21,22 …”

Section: Introductionmentioning

confidence: 99%

Antitumor agents 294. Novel E-ring-modified camptothecin–4β-anilino-4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents

Shi

Leung

et al. 2012

Bioorganic & Medicinal Chemistry

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Two conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino-4′-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties.

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Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4β-amino-4′-O-demethylepipodophyllotoxin conjugates

Cited by 28 publications

References 28 publications

Podophyllotoxin Derivatives: Current Synthetic Approaches for New Anticancer Agents

Podophyllotoxin Derivatives: Current Synthetic Approaches for New Anticancer Agents

A novel biotransformation process of 4′-demethylepipodophyllotoxin to 4′-demethylepipodophyllic acid by Bacillus fusiformis CICC 20463, Part II: process optimization

Antitumor agents 294. Novel E-ring-modified camptothecin–4β-anilino-4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents

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