Abstract
Podophyllotoxin has long been used as an active substance for cytotoxic activity. Fourteen novel biotinylated podophyllotoxin derivatives were designed, synthesized, and evaluated for cytotoxic activity for this study. The synthesized compounds were evaluated for cytotoxic activity in the following human cancer cell lines, SW480, MCF-7, A-549, SMMC-7721, and HL-60 by MTT assay. Most of them exhibited potent cytotoxic effects and compound 15 showed the highest cytotoxic activity among the five cancer cell lines tested, having its IC50 values in the range of 0.13 to 0.84 μM. Apoptosis analysis revealed that compound 15 caused obvious induction of cell apoptosis. Compound 15 significantly down-regulated the expression level of the marker proteins (caspase-3 and PARP) in H1299 and H1975 cells, activated the transcription of IRE1α, increased the expression of GRP78 and XBP-1s, and finally induced apoptosis of H1299 cells. In vivo studies showed that 15 at a dose of 20 mg/kg suppressed tumor growth of S180 cell xenografts in icr mice significantly. Further molecular docking studies suggested that compound 15 could bind well with the ATPase domain of Topoisomerase-II. These data suggest that compound 15 is a promising agent for cancer therapy deserving further research.
Highlights
Cancer is a kind of frequently-occurring disease that seriously threatens human health
Electrospray ionization mass spectrometry (ESI-MS) data were acquired on API Qstar Pulsar instrument; High resolution electrospray ionization mass spectrometry (HRESI-MS) data were obtained on LCMS-ITTOF (Shimadzu, Kyoto, Japan); All NMR spectra were recorded with Bruker AV-400 or DRX-500 or Bruker AVANCE III-600 (Bruker BioSpin GmbH, Rheinstetten, Germany) instruments, with tetramethylsilane (TMS) as an internal standard: chemical shifts (δ) are given in ppm and coupling constants (J) in Hz
PPT was regioselectively demethylated with methanesulfonic acid and sodium iodide in dichloromethane (CH2Cl2) followed by weak basic hydrolysis to give 4′ O-demethylepipodophyllotoxin 6 by means of a previously described procedure (Kamal et al, 2000)
Summary
Cancer is a kind of frequently-occurring disease that seriously threatens human health. More attention has been focused on targeting anti-cancer drugs. Development of targeted antitumor drugs, increase of bioavailability and decrease of toxicity are the key topics which are currently being studied. Research efforts in these topics have already led to the discovery of new drug leads and molecular scaffolds important for the development of novel antitumor agents. Natural products have served as important sources of lead compounds for antitumor agents which have been developed for clinical use. Many potential drugs lack tumor selectivity and often display significant toxic side effects, which hampers their development for clinical use (Holschneider et al, 1994; Bermejo et al, 2005). Molecular features overexpressed on cancer cells are being targeted
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