A series of lamellarin derivatives have been studied as topoisomerase I (Top1) inhibitors. Molecular models of the ternary complexes formed between the DNA-Top1 ensemble and lamellarin D (LMD) or camptothecin (CPT) fully intercalated into the duplex DNA have been built and studied by means of nanosecond molecular dynamics simulations in aqueous solution. Our results show that the 20-OH and 8-OH of LMD can participate in hydrogen-bonding interactions with the side chains of Glu356 and Asn722, respectively, the latter being consistent with the finding that CEM/C2 cells, which are resistant to CPT, are cross-resistant to LMD. Our models also account for the observation that LMD stabilizes Top1 cleavage at CG sites in addition to the TG sites observed for CPT and rationalize the structure-activity relationships within the series. The deleterious effect of replacing the 20-OH in LMD with a hydrogen was confirmed using a set of thermodynamic integration free energy simulations.

Sulfur heterocycles are found in low concentrations in most coalderived liquids and shale oils, and therefore, isolation of the heterocyclic sulfur fraction is necessary for individual compound Identification. In this report, a new methodology for the isolation and subsequent separation and identification of sulfur heterocycles is described and applied to selected coal liquids and shale oils. Identification was accomplished by sulfur-selective flame photometrk detection and comparison of mass spectral and chromatographic retention data of mixture components with standard reference compounds. Chromatographic retention data for 32 standard sulfur heterocycles were determined.

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.

Abstract-Total synthesis of cytotoxic marine alkaloids, lamellarins D, L, and N, has been achieved by using Hinsberg-type pyrrole synthesis and palladium-catalyzed Suzuki-Miyaura coupling of the 3,4-dihydroxypyrrole bistriflate 6 as the key reactions.The total yields of lamellarins D, L, and N from the common intermediate 6 are 54, 58, and 50%, respectively.

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Ten derivatives (3-12) of marine alkaloid lamellarin D (1) were synthesized and evaluated for cytotoxicity against a HeLa cell line in an effort to examine their structure-activity relationships. It appeared that the hydroxyl groups at positions C-8 and C-20 of 1 were important structural requirements for cytotoxic activity, while the hydroxyl group at C-14 and the two methoxy groups at C-13 and C-21 were not necessary for the activity.

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.

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