• Bulletin of the Korean Chemical Society
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• 제8권1호
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• pp.39-45
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• 1987

Daunomycin, an anthracycline antibiotic, has been found to inhibit virus multiplication and shows considerable activity against tumors. Its activity may be varied by conformational changes of daunomycin. The conformational changes are come from the pucker of D-ring and variation of environments. We have carried out conformational analyses by using empirical potential function. We found that when daunomycin is hydrated or bound to $Mg^{2+}$ ion, the minimum conformer of each state is altered from ${\alpha}$ conformer to ${\beta}$ conformer through the pathway having four local minima. Our calculated results are in good agreements with those of X-ray crystallography and biological experiments, in which metal ion inhibits the binding of daunomycin to DNA.

• Bulletin of the Korean Chemical Society
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• 제27권9호
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• pp.1359-1363
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• 2006

Novel anthracycline analogues 2-9 as potential anticancer agents were synthesized from daunomycin (1a) and doxorubicin (1b). Compounds 2, 6, and 7 were prepared by the nucleophilic displacement type esterification of a 14-bromodaunomycin (1c) with a sodium lactate, and stearic acid, respectively. Compounds 3-5 and 7-9 were prepared by the reaction of either daunomycin (1a) or doxorubicin (1b) with L-lactic and stearic acids in the presence of EDCI/PP reagents.

• Bulletin of the Korean Chemical Society
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• 제22권9호
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• pp.963-968
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• 2001

New anthracycline analogues 2-9 as potential anticancer agents have been synthesized from daunomycin (1a) and doxorubicin (1b). Compounds 2 and 6 were prepared by the nucleophilic displacement type esterification of 14-bromodaunomycin (1c) with N-benzoyl-(2R,3S)-phenylisoserine and L-pyroglutamic acid in triethyl-amine, respectively. Compounds 3, 7 and 4, 8 were prepared by the reaction of either daunomycin (1a) or doxorubicin (1b) with one equivalent of the corresponding acids in the presence of EDCI/PP. Compounds 5, 9 were obtained from 1b by reaction with 2.2 equivalents of the corresponding acids in the same manner. The cytotoxic activities of the analogues in comparison with adrimycin on cultured SNU-16 and MCF7 cell were described.

• Journal of Pharmaceutical Investigation
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• 제35권4호
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• pp.249-254
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• 2005

Multidrug resistance (MDR) of cancer cells is, at least in part, associated with the overexpression of P-glycoprotein (P-gp). Many studies have demonstrated that natural compounds obtained from fruits, vegetables, teas and medicinal plants may modulate P-gp activity. The objective of the present investigation was to examine the effect of seven natural compounds on the P-gp activity in human uterine sarcoma cell line, MES-SA/DX5. Daunomycin uptake was significantly increased by biochanin A and silymarin (p<0.0001) whereas it was reduced by morin (p<0.01). The efflux of daunomycin from the cells was significantly inhibited by biochanin A, morin, cephalotaxine, berberine (p<0.05) and silymarin (p<0.0001). Biochanin A, berberine and silymarin significantly decreased $IC_{50}$ value of daunomycin (p<0.05) while morin increased it (p<0.05). These results suggest that some natural compounds such as biochanin A and silymarin may inhibit P-gp function and can be developed as MDR reversing agents to improve the efficacy of chemotherapeutic drugs when administered concomitantly.

• 한국식품영양학회지
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• 제16권4호
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• pp.303-309
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• 2003

직ㆍ간법 변이원과 산화적 돌연변이원에 대한 송화분 추출물의 항돌연변이원성에 대하여 Ames test로 조사하였다. 메탄을 추출물을 이용하여, 10종의 돌연변이에 대한 돌연변이 억제효과를 검색한 결과 S. typhimurium TA98에서는 daunomycin, AFB$_1$과 Trp-P-1의 변이원성에 대해서만 각각 17.8, 82.2, 80.9%의 돌연변이 억제효과를, S. typhimurium TA100에서는 AFB$_1$의 변이원성에 대해서만 72.3%의 돌연변이 억제효과를 나타내었으며, S. typhimurium TA102, 104에서 t-과산화부틸과 $H_2O$$_2$의 돌연변이원성에 대한 메탄을 추출물의 돌연변이 억제 효과는 t-과산화부틸을 돌연변이원으로 한 S. typhimurium TA102에서 16.3%의 억제효과를 선택적으로 나타내었다. 따라서 메탄을 추출물을 클로르포름, 에틸아세테이트, 부탄올, 물 순으로 순차용매 분리한 다음, 이 분획물에 대한 항돌연변이원성을 검색하였다. 그 결과 S. typhimurium TA98에서 daunomycin, AFB$_1$과 Trp-P-1에 대해서 플로로포름 분획물은 각각 55.6, 93.7, 93.5%, 에틸아세테이트 분획물은 각각 11.4, 74.3, 85.2%, 부탄을 분획물에서는 10.9, -5.6, 6.8%, 물 분획물은 각각 -3.4, -3.8, 4.6%의 돌연변이 억제효과를 나타내었다. S. typhimurium TA100에서는 AFB$_1$에 대해 클로로포름 분획물과 에틸아세테이트 분획물이 각각 95.1, 62.5%의 억제효과를 나타내었으며, S. typhimurium TA102에서는 t-과산화부틸에 의해 유도된 산화적 돌연변이에 대해 클로로포름 분획물이 93.6%로 매우 강한 억제효과를 나타내었으며, 기타 분획물에서는 매우 낮은 억제효과를 나타내었다.

• Bulletin of the Korean Chemical Society
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• 제22권6호
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• pp.581-586
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• 2001

The potential anticancer agents, new anthracycline analogues (2-9) have been synthesized from the glycosides daunomycin (1a) and doxorubicin (1b). Compounds 2 and 6 were prepared by nucleophilic displacement esterification of a 14-bromodauomycin(1c) with sodium or potassium salts of butyric and all trans retinoic acid, respectively. Compounds 3 and 7 were obtained from daunomycin (1a) by direct amidation with a butyric and all trans retinoic acid in the presence of EDCI and PP, respectively. Compounds 4 and 8 were obtained from doxorubicin (1b) by reaction with the corresponding acids in the same manner. Compounds 5 and 9 were prepared from doxorubicin (1b) by acylation with two equivalents of the corresponding acids under the same reaction conditions.

• Bulletin of the Korean Chemical Society
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• 제22권6호
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• pp.587-592
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• 2001

The potential anticancer agents new anthracycline derivatives (2~9) have been synthesized from daunomycin (1a) and doxorubicin (1b) ad starting materials. Compounds 2 and 6 were prepared by the nucleophilic displacement type esterification of a 14-bromodaunomycin (1c) with a acetylsalicylic and palmitic acid in triethylamine, respectively. Compound 3 and 7 were obtained from daunomycin (1a) by direct amidation with the corresponding acids in the presence of EDCI and PP as esterification regents. Whereas 4 and 8 were prepared by reaction of doxorubicin (1b) with one equivalent of acetylsalicylic and palmitic acid using DCC/DMAP, respectively, 5 and 9 were obtained from 1b by acylation with two equivalents of the corresponding acids using EDCI/PP reagents.

• Natural Product Sciences
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• 제10권6호
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• pp.268-271
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• 2004

In order to examine their effects on the P-glycoprotein (P-gp) activity in human breast cancer cells, MCF-7/ADR, one hundred Indonesian plant extracts were screened. Among them, the five chloroform extracts of Calotropis gigantea, Curcuma aeruginosa, Merremia mammosa, Sindora sumatrana, and Zingiber cassumunar, showed the most potent P-gp inhibitory activity. When each of these extracts was treated together with the anticancer agent, daunomycin, they increased the cytotoxic activity of daunomycin up to $IC_{50}$ values of less than $6.62\;{\mu}M$, which is a value with a positive control, verapamil. Also, other 15 plant extracts exhibited significant P-gp inhibitory activity with $IC_{50}$ values between 6.62 and $13.20\;{\mu}M$. These prospective samples will be subjected to further laboratory phytochemical investigation to find active principles.

• Journal of Pharmaceutical Investigation
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• 제36권5호
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• pp.315-320
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• 2006

Silymarin showed P-glycoprptein(P-gp) inhibitory activity as much as verapamil, a well-known P-gp inhibitor, by decreasing $IC_{50}$ value of daunomycin(DNM)($16.0{\pm}0.7{\mu}M$), increasing the DNM accumulation($224.9{\pm}3.2%$), and decreasing DNM efflux($58.5{\pm}6.7%$), concurrently. In this study, we clarified the mechanism of action of silymarin for P-gp inhibitory function. First, silymarin may bind to the ATP-binding site and thus, prevent ATP hydrolysis. Second, the P-gp inhibitory activity of silymarin is not related to changing the cellular P-gp level. Third, the cytotoxicity of silymarin was increased in the presence of verapamil, reflecting that silymarin is a competent P-gp substrate against verapamil in the P-gp-overexpressed adriamycin-resistant MCF-7 breast cancer(MCF-7/ADR) cells. Conclusively, silymarin had the P-gp inhibitory activity through the action of competent binding to the P-gp substrate-binding site. Therefore, silymarin can be a good candidate for safe and effective MDR reversing agent in clinical chemotherapy by administering concomitantly with anticancer drugs.

• Journal of Pharmaceutical Investigation
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• 제34권2호
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• pp.95-99
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• 2004

One mechanism which plays a prominent role in development of multi-drug resistance seen in cancer cells is the over-expression of P-glycoprotein (P-gp). It is known that compounds found in vegetables and fruits not only have anticarcinogenic properties but may also modulate P-gp activity. The effect of some dietary components on efflux of daunomycin (DNM), a P-gp substrate, was examined in P-gp over-expressed human uterine sarcoma cell line, MES-SA/DX5. The efflux of DNM from the cells was significantly inhibited by quercetin and verapamil, but not by 1-naphtyl-isothiocyanate (NITC). The $IC_{50}$ values for DNM in MES-SA/DX5 cells were increased by flavonoids (quercetin and fisetin), but not by NITC after 72 hour incubation with dietary constituents. In conclusion, flavonoids may play a role in the modulation of P­-gp activity in human uterine sarcoma cells.