Abstract
Gibberellic acid (GA3) is a tetracyclic diterpene compound which displays interesting bioactivities. Recently, its potential use for preparing antitumor drug leads has been highlighted, and various modification methods of GA3 have been reported. Aiming at investigating GA3 derivatives with potential antitumor activities, ring distortion of GA3 under different conditions was carried out, and this was followed with amidation or substitution, yielding four series of derivatives. The chemical structure of these compounds were analyzed by 1H-NMR, 13C-NMR, HRMS, FTIR and polarimetry, and SXRD was employed to further confirm the spatial configurations of derivatives 3c and 7d. The antitumor activities of three series of derivatives were evaluated by using MTT assay and ELISA. Results shows that, among amide derivatives, compounds with a saturated linear amide showed better activity than those with an aromatic amide. Among ester derivatives, compounds with a meta-substituted benzyl group showed better activities than those with a para-substituted benzyl group. The antitumor activity of ester derivatives might possibly be linked with the inhibition of FGFR1 activation and KDR activation. Overall, this study discussed how the antitumor activity of GA3 was formed, thereby assisting the future design of more effective active GA3 derivatives.
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References
Bon DJ-YD, Mander LN, Lan P (2018) Syntheses of gibberellins A15 and A24, the key metabolites in gibberellin biosynthesis. J Org Chem 83:6566–6572
Cao R, Chen Q, Hou X, Chen H, Guan H, Ma Y, Peng W, Xu A (2004) Synthesis, acute toxicities, and antitumor effects of novel 9-substituted β-carboline derivatives. Bioorg Med Chem 12:4613–4623
Chen H, Yang Z, Ding C, Chu L, Zhang Y, Terry K, Liu H, Shen Q, Zhou J (2013) Discovery of O-alkylamino tethered niclosamide derivatives as potent and orally bioavailable anticancer agents. ACS Med Chem Lett 4:180–185
Chen J, Sun Z, Zhang Y, Zeng X, Qing C, Liu J, Li L, Zhang H (2009) Synthesis of gibberellin derivatives with anti-tumor bioactivities. Bioorg Med Chem Lett 19:5496–5499
Cross BE, Grove JF, MacMillan J, Mulholland TPC (1958) Gibberellic acid. Part VII. Struct gibberic acid J Chem Soc 0:2520–2536
Cross BE, Grove JF, Morrison A (1961) Gibberellic acid. Part XVIII. Some rearrangements of ring A. J Chem Soc 0:2498–2515
Cross BE, Markwell RE (1973) Cheminform abstract: rearrangements of the gibbane skeleton during reactions with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). J Chem Soc, Perkin Trans 1 0:1476–1487
Egbewande FA, Sadowski MC, Levrier C, Tousignant KD, White JM, Coster MJ, Nelson CC, Davis RA (2018) Identification of gibberellic acid derivatives that deregulate cholesterol metabolism in prostate cancer cells. J Nat Prod 81:838–845
Grigor’eva NY, Kucherov VF (1966) Gibberellins. Russ Chem Rev 35:850
Gu ZM, Wu YL, Zhou MY, Liu CX, Xu HZ, Yan H, Zhao Y, Huang Y, Sun HD, Chen GQ (2010) Pharicin B stabilizes retinoic acid receptor-α and presents synergistic differentiation induction with ATRA in myeloid leukemic cells. Blood 116:5289–5297
He F, Xiao W-L, Pu J-X, Wu Y-L, Zhang H-B, Li X-N, Zhao Y, Yang L-B, Chen G-Q, Sun H-D (2009) Cytotoxic ent-kaurane diterpenoids from Isodon sinuolata. PYTCAS 70:1462–1466
Huigens Iii RW, Morrison KC, Hicklin RW, Flood Jr TA, Richter MF, Hergenrother PJ (2013) A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nat Chem 5:195–202
Kassab AE, Hassan RA (2018) Novel benzotriazole N-acylarylhydrazone hybrids: design, synthesis, anticancer activity, effects on cell cycle profile, caspase-3 mediated apoptosis and FAK inhibition. Bioorg Chem 80:531–544
Kim D-K, Ryu DH, Lee JY, Lee N, Kim Y-W, Kim J-S, Chang K, Im G-J, Kim T-K, Choi W-S (2001) Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues. J Med Chem 44:1594–1602
Krow GR (2004) The Baeyer–Villiger oxidation of ketones and aldehydes. Org React 43:251–798
Lin Z-M, Guo Y-X, Gao Y-H et al. (2015) ent-kaurane diterpenoids from Chinese liverworts and their antitumor activities through Michael addition as detected in situ by a fluorescence probe. J Med Chem 58:3944–3956
Liu M, Wang W-G, Sun H-D, Pu J-X (2017) Diterpenoids from isodon species: an update. Nat Prod Rep. 34:1090–1140
Mandal PK, Ren Z, Chen X, Xiong C, McMurry JS (2009) Structure-affinity relationships of glutamine mimics incorporated into phosphopeptides targeted to the sh2 domain of signal transducer and activator of transcription 3. J Med Chem 52:6126–6141
Mander LN (1992) The chemistry of gibberellins: an overview. Chem Rev 92:573–612
Mander LN (2003) Twenty years of gibberellin research. Nat Prod Rep. 20:49–69
Mo F, Dong G (2014) ChemInform abstract: regioselective ketone α-alkylation with simple olefins via dual activation. Science 345:68–72
Mulholland TPC (1958) Gibberellic acid. Part II. Struct Synth Gibberene J Chem Soc 0:2693–2701
Sun H, Zhou Q, Fujita T, Takeda Y, Minami Y, Maronaka T, Lin Z, Shen X (1992) Rubescensin d, a diterpenoid from rabdosia rubescens. PYTCAS 31:1418–1419
Wu M-J, Wu D-M, Chen J-B, Zhao J-F, Gong L, Gong Y-X, Li Y, Yang X-D, Zhang H (2018) Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore. Bioorg Med Chem Lett 28:2543–2549
Wu Z, Zhang Y, Yang L et al. (2017) Three new ent-kaurane diterpenes from the herbs of Wedelia prostrata. J Nat Med 71:305–309
Xie L, Chen Y, Chen J, Zhang H, Liao Y, Zhou Y, Zhou L, Qing C (2018) Anti-tumor effects and mechanism of GA-13315, a novel gibberellin derivative, in human lung adenocarcinoma: an in vitro and in vivo study. Cell Mol Biol Lett 24:6
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We thank the Chinese National Natural Science Foundation (Grant 21801094), the Fundamental Research Funds for the Central Universities (China) (Grant 21617327) for generous financial support.
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Zhu, Sy., Luo, Fz. & Sun, PH. Synthesis and antitumor activity of novel gibberellin derivatives with tetracyclic diterpenoid skeletons. Med Chem Res 29, 1341–1354 (2020). https://doi.org/10.1007/s00044-020-02551-2
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DOI: https://doi.org/10.1007/s00044-020-02551-2