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1.
J Med Chem ; 63(6): 2877-2893, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-32084316

RESUMEN

As an FDA-approved drug, teniposide, was utilized in cancer treatment but was accompanied by a strong side effect in long-term clinical trials. This work discovered potential candidate drugs with low toxicity by modifying the molecule structure of teniposide through a structure-guided drug design approach. The IC50 value of novel 4,6-O-thenylidene-ß-d-glucopyranoside-(2″-acetamido, 3″-acetyl-di-S-5-fluorobenzothizole/5-fluorobenzoxazole)-4'-demethylepipodophyllotoxin (compounds 15 and 16) was 120.4-125.1 µM, which was significantly improved by around 10 times more than teniposide (11.5-22.3 µM) against healthy human cells (i.e., HL-7702, H8, MRC-5, and HMEC). In vivo studies demonstrated compounds 15 and 16 significantly suppressed the tumor growth in the HepG2 cell xenograft model without exhibiting obvious toxicity (LD50 values of 208.45 and 167.52 mg/kg), which was lower than that of teniposide (LD50 = 46.12 mg/kg). Compounds 15 and 16 caused mild γH2AX phosphorylation for low DNA toxicity and less inhibition of PI3K/Akt. Compounds 15 and 16 might be potential antitumor drugs with low toxicity.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Podofilotoxina/análogos & derivados , Tenipósido/análogos & derivados , Tenipósido/farmacología , Animales , Antineoplásicos/toxicidad , Línea Celular , Daño del ADN/efectos de los fármacos , Células Hep G2 , Humanos , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/toxicidad , Podofilotoxina/química , Podofilotoxina/farmacología , Podofilotoxina/toxicidad , Tenipósido/toxicidad
2.
Anticancer Drug Des ; 2(1): 1-12, 1987 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-3449081

RESUMEN

We have synthesized acetal and ketal derivatives of 4'-demethylepipodophyllotoxin-beta-D-glucoside (DMEPG) and epipodophyllotoxin-beta-D-glucoside (EPG) with a number of different aldehydes (viz. acetaldehyde, propionaldehyde, 2-thiophenecarboxaldehyde, 3-thiophenecarboxaldehyde, 2-furancarboxaldehyde, benzaldehyde, phenylacetaldehyde, hydrocinnamaldehyde) and acetone. The cross resistance of these compounds towards a set of Chinese hamster ovary cell mutants resistant to either podophyllotoxin (PodR mutants) or VM26 (VpmR mutants) which exhibit mutually exclusive cross-resistance patterns toward compounds that show either podophyllotoxin- or VM26-like activities have been examined. Results of our studies show that, with the exception of 2-furan derivatives, all the remaining acetals and ketals of DMEPG and EPG showed similar cross-resistance patterns towards the VpmR and the PodR mutants, as seen with VM26 and VP16-213. These results provide strong suggestive evidence that all of these derivatives (except 2-furan) possess biological activities similar to VM26 and VP16-213, and that their cellular toxicities were due to this type of activity. The VM26-like behavior of different EPG derivatives, which lack the free 4'-OH group, provide evidence that a free 4'-OH group is not essential for VM26-like activity. However, in comparison to the EPG derivatives, the corresponding DMEPG compounds showed 10- to 30-fold higher activities, indicating an enhancing effect of the free 4'-OH group on this kind of activity. Some of the newly synthesized DMEPG and EPG derivatives show higher activity in comparison to VM26 and VP16-213, and structure-activity relationship among this group of compounds is discussed.


Asunto(s)
Antineoplásicos/síntesis química , Etopósido/análogos & derivados , Podofilotoxina/análogos & derivados , Tenipósido/análogos & derivados , Antineoplásicos/farmacología , Línea Celular , Resistencia a Medicamentos , Etopósido/farmacología , Relación Estructura-Actividad , Tenipósido/farmacología
3.
Cancer Res ; 43(12 Pt 1): 5699-706, 1983 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-6580063

RESUMEN

We compared the effects of the epipodophyllotoxins 4'-demethylepipodophyllotoxin-9-(4,6-O-2-ethylidene-beta-D-glucopyranoside) (VP-16-213) and 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-beta-D-glucopyranoside) (VM-26) and several of their derivatives on cell cycle progression and viability of human leukemic lymphoblasts (CCRF-CEM). The cis-(picro)-lactone derivatives, like both VP-16-213 and VM-26, produced G2-phase arrest and cytotoxicity, but only at concentrations 100 times greater than required with the parent compounds. The epiaglycone derivative showed potent cytotoxicity: at 100 to 250 nM, it reduced cloning efficiency by 50%, an effect requiring 25 to 40 nM VM-26 and 340 to 425 nM VP-16-213. In contrast to VM-26 and VP-16-213, the epiaglycone arrested cells in M, consistent with evidence that it, like podophyllotoxin, is an inhibitor of microtubule assembly. At concentrations resulting in 50% cell kill and an increase of cells in M, however, the epiaglycone produced little change in the proportion of cells in G1 or early S phase, while podophyllotoxin produced a shift of cells to mid- and late S. The hydroxy acid derivatives, although found in detectable quantities in patients' urine and serum, were inactive in vitro. Structural differences among the compounds account for their different biochemical and cell kinetic effects and, hence, different cytotoxic activities. Because the epiaglycone is a potent compound and combines activities of both the podophyllotoxins and 4'-demethyl derivatives, further studies of its cytotoxicity are indicated.


Asunto(s)
Etopósido/toxicidad , Leucemia Linfoide/fisiopatología , Podofilotoxina/análogos & derivados , Tenipósido/toxicidad , Ciclo Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Clonales , Relación Dosis-Respuesta a Droga , Etopósido/análogos & derivados , Humanos , Cinética , Relación Estructura-Actividad , Tenipósido/análogos & derivados
4.
Cancer Chemother Pharmacol ; 7(2-3): 103-11, 1982.
Artículo en Inglés | MEDLINE | ID: mdl-7044591

RESUMEN

VP16-213, a semi-synthetic derivative of podophyllotoxin, is an effective antitumor agent in the treatment of a variety of leukemias and solid tumors. A comparison of the mechanism of action of VP16-213 and podophyllotoxin has revealed that although both drugs inhibit the uptake of nucleosides into HeLa cells, they exhibit other biological properties which are quite distinct. Podophyllotoxin is a potent inhibitor of microtubule assembly in vitro, while VP16-213 has no effect in this system. VP16-213 induces single stranded breaks in HeLa cells DNA, an effect which may be related to its antitumor activity. In contrast to VP16-213 treated cells, podophyllotoxin-treated cells maintain DNA integrity. Structure-activity relationship studies have identified some of chemical sites of VP16-213 and podophyllotoxin responsible for each of their biological properties. These studies illustrate that chemical modification of podophyllotoxin can generate derivatives which possess new and unique biological properties.


Asunto(s)
Etopósido/farmacología , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacología , Animales , Fenómenos Químicos , Química , ADN/metabolismo , Etopósido/análogos & derivados , Células HeLa , Humanos , Microtúbulos/efectos de los fármacos , Conformación Molecular , Nucleósidos/metabolismo , Relación Estructura-Actividad , Tenipósido/análogos & derivados
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