Anticancer Alkaloid Lamellarins Inhibit Protein Kinases

Abstract

Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dualspecificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors.

Recent Research Progress in Anticancer Alkaloid Lamellarin N and Lamellarin L

“…然而 2008 年 Meijer 等 [49] 提出了一种新的观点, 报道 了有些 Lamellarin 通过抑制癌细胞的蛋白激酶从而诱导 细胞凋亡. 研究中测定了 6 种不同的蛋白激酶的酶活性 (表 2) [49] , 通过非线性拟合曲线估算的 IC 50 值显示 LMN …”

“…Meijer 等 [49] 通过 CEREP 激酶选择性面板 [50] 研究了 LMN 对激酶抑制的选择性, 在有 10 µmol/L LMN 存在 的情况下测试了 44 种激酶的活性. 其中 11 种蛋白激酶 的抑制活性效果≥80% (表 3) [49] .…”

“…其中 11 种蛋白激酶 的抑制活性效果≥80% (表 3) [49] . 结果表明, LMN 并不 会抑制所有的蛋白激酶, 而是对一些主要的癌细胞蛋白 激酶(VEGFR1/2, Flt-3, PDGFR, Lck, Lyn)有一定的选择 性.…”

Aplysfistularine: a novel dibromotyrosine derivative isolated from Aplysina fistularis

“…29 Topoisomerase II inhibitors with anticancer and antiviral potential are important targets in the development of new drugs. 30 In an attempt to discover new topoisomerase inhibitors, many classes of natural products have been tested and described in the literature, including flavonoids, 31 biflavonoids, 32 diterpenes, 33 triterpenoids, 34 estilbenoids, 35 alkaloids, [36][37][38][39] naphtodianthrones, 40 naphtoquinones, 41 binaphtoquinones, 42 polyunsaturated fatty acids, 43 derivatives of the chromone nucleus, and many substances isolated from plants. 44 In medicine, compounds from the anthracycline and epipodophylotoxin classes stand out as potent topoisomerase II inhibitors.…”

A Synthesis of Lamellarins via Regioselective Assembly of 1,2,3-Differentially Substituted 5,6-Dihydropyrrolo[2,1-a]Isoquinoline Core

“…Furthermore, these lamellarins exhibit various interesting biological activities including potent antiproliferative activity against several cancer cell lines, 2g,h,j,k,m,n,3 multi-drug resistance (MDR) reversal activity, 2n,3a anti-HIV activity, 2j,3c,4 topoisomerase I inhibitory activity, 5 inhibition of mitochondrial function, 6 and protein kinases inhibitory activity. 7 Because of their unique structure and significant biological activities, lamellarins have attracted considerable attention from organic and medicinal chemists. Consequently, various synthetic methods for the preparation of lamellarins have been exploited so far.…”