<p>Glucoside Derivatives Of Podophyllotoxin: Synthesis, Physicochemical Properties, And Cytotoxicity</p>

Abstract

BackgroundWidespread concern of the side effects and the broad-spectrum anticancer property of podophyllotoxin as an antitumor agent highlight the need for the development of new podophyllotoxin derivatives. Although some per-butyrylated glucosides of podophyllotoxin and 4β-triazolyl-podophyllotoxin glycosides show good anticancer activity, the per-acetylated/free of podophyllotoxin glucosides and their per-acetylated are not well studied.MethodsA few glucoside derivatives of PPT were synthesized and evaluated for their in vitro cytotoxic activities against five human cancer cell lines, HL-60 (leukemia), SMMC-7721 (hepatoma), A-549 (lung cancer), MCF-7 (breast cancer), and SW480 (colon cancer), as well as the normal human pulmonary epithelial cell line (BEAS-2B). In addition, we investigated the structure–activity relationship and the physicochemical property–anticancer activity relationship of these compounds.ResultsCompound 6b shows the highest cytotoxic potency against all five cancer cell lines tested, with IC50 values ranging from 3.27±0.21 to 11.37±0.52 μM. We have also found that 6b displays higher selectivity than the etoposide except in the case of HL-60 cell line. The active compounds possess similar physicochemical properties: MSA > 900, %PSA < 20, ClogP > 2, MW > 700 Da, and RB > 10.ConclusionWe synthesized several glucoside derivatives of PPT and tested their cytotoxicity. Among them, compound 6b showed the highest cytotoxicity. Further studies including selectivity of active compounds have shown that the selectivity indexes of 6b are much greater than the etoposide except in the case of HL-60 cell line. The active compounds possessed similar physicochemical properties. This study indicates that active glucoside analogs of podophyllotoxin have potential as lead compounds for developing novel anticancer agents.

Antiproliferative activity, cell-cycle arrest, apoptotic induction and LC-HRMS/MS analyses of extracts from two Linum species

“…It has also been noted for its cytotoxic activity in other human cancer cell lines, HL-60, SMMC-7721, A-549, and SW480 (Zi et al. 2019 ). Podophyllotoxin and its derivatives exhibit anticancer activity, mainly due to its ability to inhibit tubulin polymerisation into microtubules (Kamal et al.…”

Design and Synthesis of Novel Podophyllotoxins Hybrids and the Effects of Different Functional Groups on Cytotoxicity

“…Depending on the chosen modern molecule hybridization strategy [ 15 , 16 ], podophyllotoxin/epipodophyllotoxin can hybridize with amino acid/peptide [ 17 , 18 ], azole [ 19 ], biotin [ 20 ], carbamate [ 21 ], chalcone [ 22 ], cinnamic acid [ 23 ], cinnamic acid [ 24 ], ferrocene [ 25 ], furan/pyrrole [ 26 ], hydroxamic acid [ 27 ], indole [ 28 ], norcantharidin [ 29 ], pyridine/pyrimidine [ 30 ], pterostilbene [ 31 ], retinoic acid [ 32 ], sugar [ 33 ], (thio)urea [ 34 ], or sulfur [ 35 ] ( Figure 1 ). These have been subjected to extensive research and have been shown to be highly active against both MDR and drug-sensitive cancer cell lines with IC 50 or GI 50 values at a nanomolar level; however, the water solubility, bioactivities, and toxicity still need to be improved.…”

Non‐targeted screening of pyranosides in Rhodiola crenulata using an all ion fragmentation‐exact neutral loss strategy combined with liquid chromatography‐quadrupole time‐of‐flight mass spectrometry

“…Geniposide from Gardenia jasminoides Ellis has potential applications in anticancer and antidepression therapeutics 3–5 . In addition, some studies have found that synthetic pyranoside derivatives of podophyllotoxin have more potent anticancer activity than podophyllotoxin itself and are currently lead compounds for the development of new anticancer drugs 6 . Thus, the screening and discovery of pyranosides not only contributes to research on natural products but may also promote pharmaceutical research and development.…”