Design, synthesis, and biological evaluation of indole carboxylic acid esters of podophyllotoxin as antiproliferative agents
- 39 Downloads
A series of indole carboxylic acid conjugates of the podophyllotoxin were synthesized and evaluated as antiproliferative agents against two human chronic myeloid leukemia cell lines. Several compounds (In-2, In-8 and In-9) not only showed antiproliferative activity against normal K562 cells but also exhibited potent antineoplastic effect against resistant K562/VCR cells. The indole-6-formyl conjugate, In-9, revealed potent cytotoxic activity against K562 and K562/VCR cell lines, with IC50 values of 0.100 ± 0.008 and 0.227 ± 0.011 μM, respectively. Preliminary mechanism studies indicated that In-9 could disrupt the microtubule network in K562/VCR cells via occupying the colchicine binding site of the tubulin. Molecular dynamics simulation results revealed that the complex of In-9 and tubulin were stable. Furthermore, In-9 induced intracellular ROS generation, apoptosis, and cycle arrest at the G2 phase by inhibition of CDKs, loss of mitochondrial membrane potential and cleavage of caspase. In-9 simultaneously induced K562/VCR cells autophagy by upregulating the levels of Beclin1 and LC3-II, and exhibited anti-MDR ability by downregulating the levels of P-gp and MRP1. Finally, In-9 activated the AMPK and JNK signaling, and inhibited the ERK, P38, and PI3K/AKT/mTOR signaling in K562/VCR cells. In silico prediction indicated that In-9 mainly obeyed Lipinski rule for druglikeness. Together, In-9 possessed potent antiproliferative activity, and may be a promising agent for the potential treatment of resistant leukemia cancer.
KeywordsPodophyllotoxin Indole carboxylic acid Anti-MDR activity Apoptosis Autophagy
This work was financially supported by the National Natural Science Foundation of China (81860622), Department of Science and Technology of Guizhou Province (1219), Joint Fund of the Department of Science and Technology of Zunyi City and Zunyi Medical University (27), and National First-Rate Construction Discipline of Guizhou Province (Pharmacy) (YLXKJS-YX-04).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Baldwin EL, Osheroff N (2005) Etoposide, topoisomerase II and cancer. Curr Med Chem 5:363–372Google Scholar
- Kim SY, Ryu JS, Li H, Park WJ, Yun HY, Beak KJ, Kwon NS, SOHN UD, Kim DS (2010) UVB-activated indole-3-acetic acid induces apoptosis of PC-3 prostate cancer cells. Anticancer Res 30:4607–4612Google Scholar
- Martínez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, Mehta MM, Wang T, Santos JH, Woychik R, Dufour E, Spelbrink JN, Weinberg SE, Zhao Y, DeBerardinis RJ, Chandel NS (2016) TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol Cell 61:199–209CrossRefGoogle Scholar
- Merzouki A, Buschmann MD, Jean M, Young RS, Liao S, Gal S, Li Z, Slilaty SN (2012) Adva-27a, a novel podophyllotoxin derivative found to be effective against multidrug resistant human cancer cells. Anticancer Res 32:4423–4432Google Scholar
- Romero DL, Olmsted RA, Poel TJ, Morge RA, Biles C, Keiser BJ, Kopta LA, Friis JM, Hosley JD, Stefanski KJ, Wishka DG, Evans DB, Morris J, Stehle RG, Sharma SK, Yagi Y, Voorman RL, Adams WJ, Tarpley WG, Thomas RC (1996) Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors. J Med Chem 39:3769–3789CrossRefGoogle Scholar
- Valentini A, Conforti F, Crispini A, De Martino A, Condello R, Stellitano C, Rotilio G, Ghedini M, Federici G, Bernardini S, Pucci D (2009) Synthesis, oxidant properties, and antitumoral effects of a heteroleptic palladium (II) complex of curcumin on human prostate cancer cells. J Med Chem 52:484–491CrossRefGoogle Scholar
- Zhang L, Liu L, Zheng C, Wang Y, Nie X, Shi D, Chen Y, Wei G, Wang J (2017a) Synthesis and biological evaluation of novel podophyllotoxin-NSAIDs conjugates as multifunctional anti-MDR agents against resistant human hepatocellular carcinoma Bel-7402/5-FU cells. Eur J Med Chem 131:81–91CrossRefGoogle Scholar