During the course of our screening program for natural product drugs effective against multidrug resistant cells by using adriamycin resistant HL-60 cells, we have discovered a new 12 membered macrolide FD-895 in the fermentation broth of Streptomyces hygroscopicus A-9561 isolated from a soil sample collected at Iriomote Island, Okinawa prefecture, Japan. FD-895 showed stronger cytocidal activities against in vitro tumor cell lines than adriamycin. FD-895 had the same IC50values against parent and adriamycin resistant HL-60 cells.A major drawback to cancer chemotherapy is that many tumors are either intrinsically resistant to the compoundor develop resistance over the course of treatment. Treatment with chemotherapeutic agents generally results only in temporary remission of tumor disease in the clinic.It is also well knownexperimentally1 '2) that mammalian cells selected for resistance to a single cytotoxic natural product drug can becomenot only resistant to the agent used but also cross-resistant to a wide range of structurally and functionally unrelated antibiotics and alkaloids. For these reasons the developmentof chemotherapeutic agents equally effective against malignant and resistant cells has been desired world wide for overcoming tumor disease. From this standpoint, we have explored natural product drugs effective against multidrug resistant cells.In the course of our screening program using adriamycin resistant HL-60cells to discover low molecular compoundsproduced in microbial fermentation broths and capable of circumventing multidrug resistance, we have discovered a new 12-membered macrolide FD-895 (Fig. 1)

New 1 8-membered macrolides FD-891 and FD-892 were discovered from the fermentation broth of Streptomyces graminofaciens A-8890 isolated from a soil sample collected at Yamanashi prefecture, Japan. They induce morophological changes of HL-60 cells at low concentration below IC5Os and have cytocidal activity against in vitro tumor cell lines. FD-891showed 2~7 times stronger activity than doxorubicin whereas FD-892 was 20~100 fold weaker than FD-891 and doxorubicin.It is well known that human promyelocytic leukemia (HL-60) cells are differentiated to macrophage or monogranucyte by DMSO, vitamin D3, retinoids, teleocidin and TPA12) and we have recently found out that their morphological changes are related to their modeof action of such biologically active compounds as brefledin, cytochlasine, vincristine, concanamycins and actinomycins (K. Mizoue and T. Okazaki, unpublished data). So, biologically active compounds screened by using HL-60 cells can be distinguished into their modeof action by the observation of morphological changes of HL-60 cells under the microscope. In the course of our screening program for low molecular compoundsinducing morphological changes of HL-60 cells in the microbial fermentation broth, we have discovered new 18-membered macrolides FD-891 and FD-892 from the cultured broth of Streptomyces graminofaciens A-8890 as shown in Fig. 1. Such 18-membered antibiotics as concanamycin 13>4) and virustomycin5'6) are

Structures of FD-891 and FD-892 were determined by extensive NMRspectral analysis as shown in Fig. 1. They belong to such 18-memberedmacrolides as concanamycins and virustomycin.In the course of our screening program for low molecular substances inducing morphological changes of HL-60, new 18-membered macrolides FD-891 and FD-892 were discovered in the fermentation broth of Streptomyce graminofaciens A-88901}. They belong to such 18-membered antibiotics as concanamycins2'3) and virustomycin4'5). Their biological properties are similar to those of 18-membered antibiotics1}. Their structures were determined by extensive NMRanalysis as shown in Fig. 1. This paper deals with their structural elucidation. Results and DiscussionStructure of FD-891 The physico-chemical properties of FD-891 are shown in Table 1. The UVspectrum of FD-891 showed the absorption at 270 nm due to a diene system conjugated with a carbonyl group. The bands at 3400 and

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