In order to design new antitumor drugs and study the relationship between antitumor and antioxidative activity of spin-labeled derivatives of podophyllotoxin, five novel pyrroline spin-labeled 4β-N-substituted-amino acid-4′-O-demethylepipodo-phyllotoxin compounds (11a-e) (Scheme 2) were synthesized and evaluated. Their cytotoxicity against three tumor cell lines (human lung carcinoma A-549, human leukemia cell HL-60 and multiple myeloma RPMI-8226) has been evaluated using a MTT-based assay in vitro. Also, we determined malondialdehyde (MDA) in liver and kidney homogenate of SD rats by the TBA method. The five new compounds showed either superior or comparable inhibitory activity against A-549, HL-60 and RPMI-8226 cell lines compared with etoposide (VP-16, 2), and all the tested compounds showed more significant antioxidant activities than VP-16. Furthermore, the partition coefficients were measured and preliminary structure-activity relationships are presented.
ImbertT. (1998) Discovery of podophyllotoxins. Biochimie, 80, 207–222.
3.
HandeK. (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. European Journal of Cancer, 34, 1514–1521;
4.
JardineI. (1980) Podophyllotoxins. In: Anticancer Agents Based on Natural Product Models. Academic Press, New York, pp. 319–351.
5.
IssellB. (1982) The podophyllotoxin derivatives VP16-213 and VM26. Cancer Chemotherapy and Pharmacology, 7, 73–80;
6.
GordalizaM, CastroM, Del CorralJ, FelicianoA. (2000) Antitumor properties of podophyllotoxin and related compounds. Current Pharmaceutical Design, 6, 1811–1839.
7.
ShahJ, ChenJ, ChowD. (1989) Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide. Pharmaceutical Research, 6, 408–412.
8.
BudmanD. (1996) Early studies of etoposide phosphate, a water-soluble prodrug. [Journal Article, Research Support, Non-U.S. Gov't, Review]. Seminar in Oncology, 23, 8–14.
9.
GrecoF, HainsworthJ. (1996) Clinical studies with etoposide phosphate. [Clinical Trial, Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial]. Seminar in Oncology, 23, 45–50.
10.
LeeK. (1999) Novel antitumor agents from higher plants. Medicinal Research Reviews, 19, 569–96;
11.
WangZ, KuoY, SchnurD, BowenJ, LiuS, HanF, ChangJ, ChengY, LeeK. (1990) Antitumor agents. 113. New 4. beta.-arylamino derivatives of 4′-O-demethylepipodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II. Journal of Medicinal Chemistry, 33, 2660–2666;
12.
DucaM, Guianvarc'hD, MeresseP, BertounesqueE, DauzonneD, Kraus-BerthierL, ThirotS, LeonceS, PierreA, PfeifferB. (2005) Synthesis and biological study of a new series of 4-demethylepipodophyllotoxin derivatives. Journal of Medicinal Chemistry, 48, 593–603.
13.
SosnovskyG, LiS. (1985) In the search for new anticancer drugs. XII: Synthesis and biological evaluation and biological evaluation of spin labeled nitrosoureas. Life Sciences, 36, 1479–1483.
14.
AntosiewiczJ, PopinigisJ, WozniakM, DamianiE, CarloniP, GreciL. (1995) Effects of indolinic and quinolinic aminoxyls on protein and lipid peroxidation of rat liver microsomes. Free Radical Biology and Medicine, 18, 913–917;
15.
HahnS, SullivanF, DeLucaA, BacherJ, LiebmannJ, KrishnaM, CoffinD, MitchellJ. (1999) Hemodynamic effect of the nitroxide superoxide dismutase mimics. Free Radical Biology and Medicine, 27, 529–535.
16.
KonovalovaN, D'iachkovskaiaR, VolkovaL, VarfolomeevV. (1996) Nitroxyl radical Tempol as a modulator of toxic and antineoplastic effect of 6-mercaptopurine. Voprosy Onkologii, 42, 57–63.
17.
TianX, ZhangF, LiW. (2002) Antitumor and antioxidant activity of spin labeled derivatives of podophyllotoxin (GP-1) and congeners. Life Sciences, 70, 2433–2443;
18.
JinY, ChenS, TianX. (2006) Synthesis and biological evaluation of new spin-labeled derivatives of podophyllotoxin. Bioorganic & Medicinal Chemistry, 14, 3062–3068.
19.
WongL, SchwenkR, HsiaJ. (1974) New synthesis of nitroxyl radicals of the piperidine and tetrahydropyridine series. Canadian Journal of Chemistry, 52, 3381–3383;
20.
HankovszkyH, HidegK, LexL. (1980) Nitroxyls; VII. Synthesis and reactions of highly reactive 1-oxyl-2, 2, 5, 5-tetramethyl-2, 5-dihydropyrrole-3-yl methyl sulfonates. Synthesis, 11, 914–916.
21.
CouetW, BraschR, SosnovskyG, LukszoJ, PrakashI, GnewuchC, TozerT. (1985) Influence of chemical structure of nitroxyl spins labels on their reduction by ascorbic acid. Tetrahedron, 41, 1165–1172;
22.
NaikN, BraslauR. (1998) Synthesis and applications of optically active nitroxides. Tetrahedron, 54, 667–696.
23.
LeeK, ImakuraY, HarunaM, BeersS, ThurstonL, DalH, ChenCH. (1989) Antitumor agents, 107. New cytotoxic 4-alkylamino analogues of 4′-demethy-epipodophyllotoxin as inhibitors of human DNA topoisomerase. Journal of Natural Products, 52, 606–613;
24.
ZhouX, WangZ, ChangJ, ChenH, ChengY, LeeK. (1991) Antitumor agents. 120. New 4-substituted benzylamine and benzyl ether derivatives of 4′-O-demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomerase II. Journal of Medicinal Chemistry, 34, 3346–3350.
25.
OhkawaH, OhishiN, YagiK. (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95, 351–358.
26.
SosnovskyG. (1990) The quest for a predictive design of anticancer drugs. Pure & Applied Chemistry, 62, 289–294.
