Sesquiterpene Aminoquinones, from a Marine Sponge, Induce Erythroid Differentiation in Human Chronic Myelogenous Leukemia, K562 Cells

Abstract

Despite the various cancer therapeutic methods such as chemotherapy, which are being carried out clinically, cancer remains to be a serious and, in most cases, fatal disease. Chemotherapeutic drugs affect not only tumor cells but also proliferative normal cells such as bone marrow cells and result in serious side effects. To solve this problem, several other alternative therapeutic methods are being developed. The differentiation-induction therapy, in which tumor cells are differentiated to normal cells, seems to be one promising therapy. As a good example of differentiation inducer, ATRA (all-trans-retinoic acid) has shown superior therapeutic effect on acute promyelocytic leukemia (APL), which is unresponsive to conventional chemotherapeutic drugs.1) However, several kinds of leukemia such as human chronic myelogenous leukemia (CML) are unresponsive to ATRA. So, development of new differentiation inducers has been required.As a part of our exploratory research of bioactive substances from marine organisms, we have been searching for new differentiation inducers to tumor cells and have found several inducers to ATRA-nonresponsive CML (K562 cells) or murine neuroblastoma (Neuro 2A cells) from marine sponges.2-4) Recently, we have isolated from a marine sponge 5) a sesquiterpene aminoquinone, smenospongine (4), which induces differentiation of K562 cells into erythroblasts. Study on its action mechanism showed that smenospongine induced arrest of the cell cycle at the G1 phase and increased expression of p21 protein, a Cip1/Waf1 cdk (cyclin dependent kinase) inhibitor.5) This interesting action of smenospongine led us to continue further study, and we isolated ten sesquiterpene quinones/phenol analogues from the same marine sponge, including a new compound named 5-epi-smenospongorine (1). In this paper, the structure-activity relationship of these sesquiterpene quinones is discussed. Results and DiscussionChemical Structures of 5-epi-Smenospongorine (1) and the Analogues The nine sesquiterpene quinone/phenols (2-10) together with a new compound named 5-epismenospongorine (1) were isolated from the marine sponge Dactylospongia elegans. (Fig. 1) Compounds 2-10 were identified as smenospongorine, 6,7) 5-epi-smenospongine, 6,8) smenospongine, 6,7,9) C-NMR signals due to the decalin part and the quinone part in 1 were closely similar to those of 5-epi-smenospongidine (5) 6) and smenospongorine (2), 7) respectively. Then, it is presumed that compound 1 is a hybrid of 5-epismenospongidine (5) and smenospongorine (2).8) This presumption that compound 1 is an epimer at the C-5 position of smenospongorine (2) was further confirmed by nuclear overhauser effect spectroscopy (NOESY) analysis of both compounds 1 and 2. Thus, the correlations between H-12 and H-10 for compound 1 and between H-12 and H-14 for compound 2 were found. Based on these evidences, compound 1 was determined as 5-epi-smenospongorine as shown in Fig. 1. A new sesquiterpene aminoquinone, 5-epi-smenospongorine, together with nine known sesquiterpene quino...

Comparison of the Biological Properties of Several Marine Sponge-Derived Sesquiterpenoid Quinones

“…They found that the quinone and amine groups are essential for activity (low μM), but that the configuration at C-5 is not important. The profile observed for PLA 2 inhibitory activity in our study was similar to that reported by Aoki et al [35] where the two hydroxyquinones tested were active, two of the three aminoquinones were active and the one hydroquinone tested was inactive. Further studies are in progress in order to evaluate the potential anti-inflammatory activity of these compounds.…”

“…Aoki et al recently reported a structure-activity relationship study of ten sesquiterpene quinone/ hydroquinones with respect to their ability to induce differentiation of K562 cells into erythroblasts [35]. They found that the quinone and amine groups are essential for activity (low μM), but that the configuration at C-5 is not important.…”

Recent advances in 1,4-benzoquinone chemistry

“…Stahl et al 70 described the first enantioselective total synthesis of the nakijiquinones and their biological evaluation. Besides ilimaquinone (54), 71 smnenospongines (55-57), 72 metachromins L, N, P (58-60) 73 and mamanuthaquinone (61) 74 display antimicrobial, antiviral and cytotoxic activities.…”

Marine sponge‐derived smenospongine preferentially eliminates breast cancer stem‐like cells via p38/AMPKα pathways

“…In leukemia cells, Sme extensively involves in promoting erythroid differentiation in human chronic myelogenous leukemia and inhibiting proliferative activity against different leukemia cells through induction of G1 arrest or apoptosis 32, 33, 34. Recent studies have further shown that Sme exhibits antiproliferative and antiangiogenic activities on solid tumor cells 35.…”