Synthesis and Structure−Activity Relationship Study of Potent Cytotoxic Analogues of the Marine Alkaloid Lamellarin D

Abstract

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogues of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB-231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data, the SAR study concluded that more than 75% of the open-chain Lam-D analogues tested showed cytotoxicity in a low micromolar GI50 range.

Lamellarin D Bioconjugates I: Synthesis and Cellular Internalization of PEG-Derivatives

“…positions of Lam-D (3,19), and their essential role for cytotoxicity and topoisomerase I inhibition (3), in this study, the free OH groups were chosen for attachment the PEG moiety. As esters readily hydrolyze under physiological conditions, our group envisioned that these derivatives would enable gradual release of the drug.…”

Recent Advances in Lamellarin Alkaloids: Isolation, Synthesis and Activity

“…These data reveal that the complete structure is crucial for biological activity, despite being less soluble in biological media than simpler molecules. In a general overview, oxidized derivatives showed greater activity than the corresponding reduced analogs [34]. These data reveal that the complete structure is crucial for biological activity, despite being less soluble in biological media than simpler molecules.…”

“…Several diversely substituted pyrroloisoquinolines were thus prepared [29]. Table 5) [34]. Other C4-C5-bisarylpyrrole-2-carboxylate simplified analogs were synthesized by Banwell et al [35].…”

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

“…Most of the lamellarin D derivatives with an open lactone ring were found to be considerably less cytotoxic than lamellarin D, except when a lactonization potential is preserved. In this case, a marked toxicity toward A-549 lung carcinoma, HT-29 colon carcinoma, and MDA-MD-231 breast adenocarcinoma cells was maintained [59]. Another general observation is that the planarity of the pharmacophore conferred by the double bond between carbons 5 and 6 in the quinoline B-ring is a crucial element for cytotoxicity and TOPO I inhibition; when this double bond is lacking, as in lamellarin K (79), for example, the planar conformation no longer exists and the drug loses its capacity to interfere with TOPO I.…”