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...