Glucoside Derivatives Of Podophyllotoxin: Synthesis, Physicochemical Properties, And Cytotoxicity

Abstract

Background: Widespread 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.

Methods: A 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.

Results: Compound 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.

Conclusion: We 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.

Keywords: cytotoxicity; glucoside; physicochemical properties; podophyllotoxin; synthesis.

Scheme 1

Structure of compounds 1–6: podophyllotoxin (1), etoposide (2), teniposide (3), etopophos (4), NK-611 (5), and podophyllotoxin glucosides (6).

Scheme 2

Synthesis of glucoside derivatives of PPT 6a – 6d. Reagents and conditions: (A) Ac₂O, sodium acetate, 100°C, 20 mins, ~99%; (B) NH₃⋅H₂O, CH₃CN, rt, overnight, 46%; (C) BF₃⋅Et₂O, CH₂Cl₂, −78°C to rt, 58–62%; (D) CH₃ONa, CH₃OH, 2 hrs, rt, 78–80%.

Figure 1

Inhibitory effects of podophyllotoxin derivatives on cancer cells. (A–D) The inhibitory effects of compounds 6a – 6d on HL-60 (leukemia), SMMC-7721 (hepatoma), A-549 (lung cancer), MCF-7 (breast cancer), and SW480 (colon cancer) cells, as evaluated by the MTT assay.

Figure 2

Chemical stability investigation of compounds 1 and 6b.