Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant

Fukuda, Tsutomu; Umeki, Teppei; Tokushima, Keiji; Gao, Xiang; Yoshida, Yuki; Ishibashi, Fumito; Oku, Yusuke; Nishiya, Naoyuki; Uehara, Yoshimasa; Iwao, Masatomo

doi:10.1016/j.bmc.2017.10.030

Cited by 26 publications

(22 citation statements)

References 45 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to osimertinib, Lam14 maintained its efficacy against EGFR del ex19/T790M/C797S at a similar level to its inhibitory activity against EGFR del ex19/T790M (Figure 4B,C). Lam14 potently inhibits the activation of the mutant EGFR kinase in comparison WT EGFR kinase in vitro 38 . The Ba/F3 model also showed that mutant EGFR del ex19/T790M/C797S is more sensitive to Lam14 than WT EGFR (Figure 4C,D).…”

Section: Resultsmentioning

confidence: 88%

“…Modifying the A‐ring of LamN altered target orientation and inhibited the EGFR T790M/L858R mutant at a low nanomolar IC 50 in vitro (8.9 nM) 38 . To examine the target transition among lamellarin derivatives at the cellular level, two bioinformatic approaches were adopted.…”

Section: Resultsmentioning

confidence: 99%

“…These findings suggest that the Lam scaffold is a unique structural motif that can be used to design selective inhibitors of protein kinases. By derivatizing a dual Topo I and protein kinase inhibitor, LamN, we generated a potent noncovalent EGFR‐TKI, Lam14, that shows in vitro efficacy against the T790M gatekeeper mutation 38 …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor

et al. 2021

Self Cite

View full text Add to dashboard Cite

The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third‐generation EGFR‐tyrosine kinase inhibitor (EGFR‐TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR‐TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor‐like biological activity of lamellarin N into kinase inhibitor‐like activity. Ba/F3 and PC‐9 cells expressing the EGFR in‐frame deletion within exon 19 (del ex19)/T790M/C797S triple‐mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple‐mutant EGFR PC‐9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple‐mutant EGFR PC‐9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR‐TKI that prevents the development of cross‐resistance against known drugs in this class.

show abstract

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Methyl 5-(2,2-difluorobenzo[d] [ 1 , 3 ] dioxol-5-yl)-1H-pyrrole-2-carboxylate ( 2u ) The general Suzuki procedure B was applied to methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrrole-2-carboxylate (251 mg, 1 mmol, 1 equiv) and 5-bromo-2,2-difluorobenzo[d] [ 1 , 3 ]dioxole (204 µL, 356 mg, 1.5 mmol, 1.5 equiv) for 48 h. Colorless solid; yield: 224 mg (80%); mp 171–173 °C; R f = 0.30 (hexanes–CH 2 Cl 2 1:3). FT-IR (ATR): 3315, 3142, 2961, 1680, 1619, 1514, 1472, 1441, 1387, 1288, 1241, 1060, 1044, 1003, 964, 938, 826, 765, 704, 634 cm −1 .…”

Section: Methodsmentioning

confidence: 99%

“…5-Aryl 1 H -Pyrrole-2-carboxylate esters constitute an important class of pyrrole derivatives [ 1 , 2 ]. This structural motif is present in several natural products and their analogs such as Lamellarins [ 3 , 4 , 5 , 6 , 7 ] (topoisomerase I inhibitor, MDR reversal agent, and anti-HIV agent), and arylated hymenialdisine [ 8 , 9 ] (ChK2 inhibitor), as well as in several other biologically active compounds with anti-HIV [ 10 , 11 , 12 , 13 , 14 ], antibacterial [ 15 ], antimitotic [ 16 ], and cytotoxic [ 17 ] activities ( Figure 1 ). 5-Aryl 1 H -Pyrrole-2-carboxylate esters and their derivatives have also found applications, for example, as organic fluorescent materials [ 18 , 19 ], anion receptors/molecular logic gates [ 20 ], and as building blocks for metal organic frameworks [ 21 ] and helical asymmetric architectures [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C–H Borylation and Suzuki Coupling

et al. 2020

View full text Add to dashboard Cite

A convenient two-step preparation of NH-free 5-aryl-pyrrole-2-carboxylates is described. The synthetic route consists of catalytic borylation of commercially available pyrrole-2-carboxylate ester followed by Suzuki coupling without going through pyrrole N–H protection and deprotection steps. The resulting 5-aryl substituted pyrrole-2-carboxylates were synthesized in good- to excellent yields. This synthetic route can tolerate a variety of functional groups including those with acidic protons on the aryl bromide coupling partner. This methodology is also applicable for cross-coupling with heteroaryl bromides to yield pyrrole-thiophene, pyrrole-pyridine, and 2,3’-bi-pyrrole based bi-heteroaryls.

show abstract

Formation of 3,4‐Diarylpyrrole‐ and Pyrrolocoumarin Core of Natural Marine Products via Barton–Zard Reaction and Selective O‐Demethylation

et al. 2020

View full text Add to dashboard Cite

A metal-free approach to 3,4-diarylpyrrole-2-carboxylate and pyrrolocoumarin cores of lamellarins and related natural products based on Barton-Zard reaction of nitrostilbenes with ethyl isocyanoacetate was developed. In the case of diarylpyrrole-2-carboxylates with a 3-(o-methoxyphenyl)[a] N. Scheme 1. Formation of the lactone fragment. Results and Discussion An Approach to 3,4-Diarylpyrrole CoreSurprisingly, a Barton-Zard reaction [21] (that is, base-catalyzed reaction of nitroalkenes with alkyl isocyanoacetate) has not yet been reported for synthesis of the pyrrole core of lamellarins and related compounds, [22] though such reaction with 1,2-diaryl-1-nitroethylenes should be a straightforward way of accessing 3,4-diarylpyrrole-2-carboxylates as key structural fragments of the lamellarins, ningalins, and lukianols. Scheme 2. Synthesis of Lamellarin Q Et ester. i: CNCH 2 COOEt, EtOH, K 2 CO 3 , 87 %; ii: BBr 3 (3 equiv.), CH 2 Cl 2 , 0°C, 85 %; iii: BBr 3 (2 equiv.), CH 2 Cl 2 , 0°C, 63 %; iv: 4-HOC 6 H 4 CHO, MeOH, MeNH 2 ·HCl, NaHCO 3 ; v: CNCH 2 COOEt, EtOH, K 2 CO 3 . EurJOCEuropean Journal of Organic Chemistry demethylated under the action of BBr 3 (3 equiv.) to afford lamellarin Q Et ester (Scheme 2):Noteworthy, the reaction in the presence of 2 equiv. of BBr 3[24] demonstrated a pronounced selectivity: it produced a mixture of partially demethylated products 2b and 2c in ca. 1:4 ratio. The structure of a minor product (2b) was confirmed by its alternative synthesis from 2-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1-nitroethene 1b (Scheme 2) (the latter was, in turn, prepared by condensation of 4-methoxyphenylnitromethane and 4-hydroxybenzaldehyde).Demethylation of methyl 3,4-bis(4-methoxyphenyl)pyrrole-2carboxylate 3a with excess BBr 3 (3 equiv.) furnished lamellarin Q (Scheme 3, Figure 2): Scheme 3. Synthesis of Lamellarin Q. i: BBr 3 (3 equiv.), CH 2 Cl 2 , 0°C, 84 %; ii: MeONa, reflux, 84 %; iii: CNCH 2 COOEt, MeOH, K 2 CO 3 , 89 %.Figure 2. Molecular structure of Lamellarin Q·MeCN (50 % ellipsoids).

show abstract

Design, synthesis, and evaluation of A-ring-modified lamellarin N analogues as noncovalent inhibitors of the EGFR T790M/L858R mutant

Cited by 26 publications

References 45 publications

Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor

Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor

Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C–H Borylation and Suzuki Coupling

Formation of 3,4‐Diarylpyrrole‐ and Pyrrolocoumarin Core of Natural Marine Products via Barton–Zard Reaction and Selective O‐Demethylation

Contact Info

Product

Resources

About