Synthesis of Rocaglamide Hydroxamates and Related Compounds as Eukaryotic Translation Inhibitors: Synthetic and Biological Studies

Abstract

The rocaglates/ rocaglamides are a class of natural products known to display potent anticancer activity. One such derivative, silvestrol, has shown activity comparable to taxol in certain settings. Here, we report the synthesis of various rocaglamide analogs and identification of a hydroxamate derivative (-)-9 having activity similar to silvestrol in vitro and ex vivo for inhibition of protein synthesis. We also show that (-)-9 synergizes with doxorubicin in vivo to reduce Eμ-Myc driven lymphomas.

Flavaglines: Potent Anticancer Drugs that Target Prohibitins and the Helicase eIF4A

“…The impressive antitumor efficacy may be explained by the requirement for eIF4A signaling in these cancer cells, where it is constitutively activated. This in vivo anticancer activity was further substantiated by several complementary studies, which suggest that flavaglines may find an optimal use in association with another anticancer drug to potentiate their activity and prevent resistance (Table 1) [2,4,7,20,22,24,25,28,[37][38][39][40]101]. Importantly, in all of these preclinical studies, flavaglines did not show any sign of toxicity in mice.…”

“…daily for 5 days [37] 7 RPMI-8226 myeloma Absence of significant effect 0.2 mg/kg i.p., 5 days/ week for 3 weeks equals maximum tolerated dose [38] Silvestrol (9) L3.6pl pancreatic cancer and RPMI-8226 myeloma Absence of significant effect 0.2 mg/kg i.p., 5 days/ week equals maximum tolerated dose [38] Silvestrol (9) Eµ-Myc/(myr)Akt lymphoma Potentiation of the effects of doxorubicin (otherwise inactive): increase in lifetime by 7 days (used in monotherapy, silvestrol did not display any significant effect) 0.2 mg/kg i.p. daily for 5 days [37] Silvestrol (9) P388 leukemia Increase in lifespan corresponding to a T/C of 150% 2.5 mg/kg i.p. for 5 days [39] Silvestrol (9) PC3 prostate cancer Reduction of the mean tumor weight by 60% 3 mg/kg i.p., three times per week for 3 weeks [101] Silvestrol (9) Pten + /Eµ-Myc lymphoma Potentiation of the effects of doxorubicin: increase in lifetime by 5 days compared with doxorubicin alone (silvestrol alone was inactive) 0.2 mg/kg i.p.…”

“…Since the release of the preceding reviews, three articles published in the Journal of Medicinal Chemistry from John Porco's laboratory, Martin Tremblay's group at Infinity Pharmaceuticals and our own laboratory, have revealed critical SAR data regarding the anticancer and cytoprotective activities of flavaglines [37,38,43]. Tremblay and colleagues explored the anticancer properties of several silvestrol derivatives and concluded that this class of flavaglines, substituted by a pseudosugar, display poor absorption, distribution, metabolism and excretion properties that severely limit their development toward clinical applications [38].…”

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

“…SAR studies have revealed that analogues lacking the dioxanyl moiety have a significant decreased affinity for MDR1 [152]. Some of these derivatives are comparable to silvestrol with respect to targeting eIF4A and extending tumor-free survival in preclinical mouse lymphoma models, while also having the added benefit of a simplified synthesis strategy [152,153].…”

558 RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

“…1d, f-i). EIF4E and eIF4A1 are required to maintain T-ALL and cells expressing a constitutive 4E-BP1 allele (4E-BP1(4A)) 21 or an eIF4A1 knockdown construct are rapidly eliminated from mixed populations ( Silvestrol and a synthetic analogue (±)-CR-31-B (CR) inhibit eIF4A1/2 11,22 . A reporter assay confirms that both drugs preferentially block cap-dependent translation of renilla luciferase compared to firefly luciferase expressed from the HCV IRES ( Figure 2a Table 2).…”