Biomaterial Database

Synthesis and biological activities of the C-4 esters of 4'-demethylepipodophyllotoxin. 1987

R S Gupta, and P C Chenchaiah

Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.

To investigate the structure-activity relationship among podophyllotoxin (POD) derivatives, a number of different esters of the C-4 hydroxyl group of 4'-demethylepipodophyllotoxin (DMEP) and 4'-benzyloxycarbonyl-4'-demethylepipodophyllotoxin have been synthesized. Some of these esters contained the same R groups of aldehydes (e.g. methyl, ethyl, 2-thiophene, phenyl) which, when condensed to either 4'-demethylepipodophyllotoxin-beta-D-glucoside or epipodophyllotoxin-beta-D-glucoside, have yielded compounds with VM26-like activities. The cross-resistance patterns of the DMEP esters towards a set of either POD-resistant (PodR) or VM26-resistant (VpmR) mutants of Chinese hamster ovary (CHO) cells which exhibit highly specific cross-resistance patterns toward POD- or VM26-like compounds have been determined. The PodR mutants were found to exhibit proportionately increased cross resistance toward the various DMEP esters, whereas no increased resistance was observed for the VpmR mutants. The observed cross resistance behavior of the DMEP esters strongly suggests that all of these analogues possess similar biological activity as POD and that none of these act in the same manner as VM26 or VP16-213. Treatment of CHO cells with the various DMEP esters caused a large increase in the mitotic index of cells, which supports the above inference. The POD-like behavior of different DMEP esters indicates that specific attachment of the R group to the C-4 glucoside moiety is required for VM26-like activity. The structure-activity studies on various DMEP esters provide information regarding the role of substituents at the C-4 and C-4' positions on POD-like activity of the compounds.

UI	MeSH Term	Description	Entries
D008940	Mitotic Index	An expression of the number of mitoses found in a stated number of cells.	Index, Mitotic,Indices, Mitotic,Mitotic Indices
D011034	Podophyllotoxin	A lignan (LIGNANS) found in PODOPHYLLIN resin from the roots of PODOPHYLLUM plants. It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives.	Epipodophyllotoxin,CPH86,Condyline,Condylox,Podocon-25,Podofilm,Podofilox,Podophyllotoxin, (5R-(5 alpha,5a alpha,8a alpha,9 alpha))-Isomer,Podophyllotoxin, (5R-(5 alpha,5a alpha,8a alpha,9 beta))-Isomer,Podophyllotoxin, (5R-(5 alpha,5a alpha,8a beta,9 alpha))-Isomer,Podophyllotoxin, (5R-(5 alpha,5a beta,8a alpha,9 beta))-Isomer,Wartec,Warticon
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D004351	Drug Resistance	Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.	Resistance, Drug
D004952	Esters	Compounds derived from organic or inorganic acids in which at least one hydroxyl group is replaced by an –O-alkyl or another organic group. They can be represented by the structure formula RCOOR’ and are usually formed by the reaction between an acid and an alcohol with elimination of water.	Ester
D005047	Etoposide	A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.	Demethyl Epipodophyllotoxin Ethylidine Glucoside,Celltop,Eposide,Eposin,Eto-GRY,Etomedac,Etopos,Etoposide Pierre Fabre,Etoposide Teva,Etoposide, (5S)-Isomer,Etoposide, (5a alpha)-Isomer,Etoposide, (5a alpha,9 alpha)-Isomer,Etoposide, alpha-D-Glucopyranosyl Isomer,Etoposido Ferrer Farma,Exitop,Lastet,NSC-141540,Onkoposid,Riboposid,Toposar,VP 16-213,VP-16,Vepesid,Vépéside-Sandoz,Eto GRY,Etoposide, alpha D Glucopyranosyl Isomer,NSC 141540,NSC141540,Teva, Etoposide,VP 16,VP 16 213,VP 16213,VP16,Vépéside Sandoz,alpha-D-Glucopyranosyl Isomer Etoposide
D000970	Antineoplastic Agents	Substances that inhibit or prevent the proliferation of NEOPLASMS.	Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013713	Teniposide	A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent cells from entering into the mitotic phase of the cell cycle, and lead to cell death. Teniposide acts primarily in the G2 and S phases of the cycle.	Demethyl Epipodophyllotoxin Thenylidine Glucoside,NSC-122819,Teniposide, (5a alpha,9 alpha(S*))-Isomer,VM-26,Vumon,NSC 122819,NSC122819,VM 26,VM26