Design and Synthesis of Lamellarin D Analogues Targeting Topoisomerase I

Abstract

A general synthetic route to rationally designed lamellarin D analogues, 1-dearyllamellarin D (1) and 1-substituted 1-dearyllamellarin D (2), has been developed. The key pentacyclic intermediate 22 was prepared by palladium-catalyzed direct arylation of 12, which in turn was synthesized via C-2-selective lithiation of 15 followed by palladium-catalyzed cross-coupling as the key reactions. Compound 22 was converted to a wide range of C-1-substituted analogues 2 via regioselective electrophilic substitution and palladium-catalyzed cross-coupling reactions.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…Lamellarin I (38) was the most potent polycyclic pyrrole-containing alkaloid described as a MDR modulator. Methoxy-derivatives of lamellarin D (37), lamellarin K (39), and lamellarin N (40) (Figure 8), exhibit not only potent cytotoxicity against MDR cancer cell lines, but also reverse their MDR at non-cytotoxic concentration [100,101]. Compound 38 was 16 folds more sensitive than verapamil in doxorubicin-resistant Lo Vo/Dx cell line, and it increased the cytotoxicity of doxorubin, vinblastine, and daunorubicine in MDR cells because it directly inhibited P-gp pump function and increased drug accumulation in the cells [102].…”

Rotational Energy Barrier around the C1–C11 Single Bond in Lamellarins: A Study by Variable-Temperature NMR

“…34 The known pentacyclic compound (3) 34 was brominated regioselectively at C1 with N-bromosuccinimide (NBS) to give 4 in 89% yield. Subsequent Suzuki-Miyaura coupling of The free energy barriers to rotation around C1-C11 single bond in 1a and 1b were calculated using these experimental data.…”

Synthesis and Biological Activity of Lamellarin Alkaloids: An Overview

“…Steglich solved this problem and achieved the first total synthesis of lamellarin L (Scheme 15). 53 The differentiation was achieved by coupling ethyl ester (85) and methyl ester (86). Thus, deprotonation of 85 and sequential treatment with 86 and 88 gave unsymmetrically substituted pyrrole (89) in one pot.…”

“…86 The synthesis of the 1-dearylated key intermediate (215) is shown in Scheme 28. N-Benzenesulfonylpyrrole (207) was brominated at C3 by treatment with 1.0 equiv of bromine in refluxing acetic acid to give 208.…”