Author: Doki, Noriko ; Seki, Fumiya ; Hachiro, Yoshifumi ; Kanda, Risa ; Hara, Takahiko ; Yagi, Takuya ; Nuriya, Hideko ; Maki, Shojiro A ; Goyama, Susumu ; Kitamura, Toshio ; Miyashita, Kazuya ; Kagaya, Noritaka ; Shin-Ya, Kazuo ; Nakata, Chihiro ; Kitada, Nobuo ; Hoyano, Shota ; Higashi, Tomoya ; Najima, Yuho ; Takechi, Azusa ; Yoshida, Chihiro ; Kobayashi, Takeshi ; Toya, Takashi ; Tanegashima, Kosuke

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most frequently occurring cancers in children and is associated with a poor prognosis. Here, we performed large-scale screening of natural compound libraries to identify potential drugs against T-ALL. We identified three low-molecular-weight compounds (auxarconjugatin-B, rumbrin, and lavendamycin) that inhibited the proliferation of the T-ALL cell line CCRF-CEM, but not that of the B lymphoma cell line Raji in a low concentration range. Among them, auxarconjugatin-B and rumbrin commonly contained a polyenyl 3-chloropyrrol in their chemical structure, therefore we chose auxarconjugatin-B for further analyses. Auxarconjugatin-B suppressed the in vitro growth of five human T-ALL cell lines and two T-ALL patient-derived cells, but not that of adult T-cell leukemia patient-derived cells. Cultured normal T cells were several-fold resistant to auxarconjugatin-B. Auxarconjugatin-B and its synthetic analogue Ra#37 depolarized the mitochondrial membrane potential of CCRF-CEM cells within 3 h of treatment. These compounds are promising seeds for developing novel anti-T-ALL drugs.

01 Oct 2023·Bioorganic & Medicinal Chemistry Letters

Synthesis and anti-tumor activities in human leukemia-derived cells of polyenylpyrroles with a methyl group at the conjugated polyene terminus

Article

Author: Obata, Rika ; Hachiro, Yoshifumi ; Higashi, Tomoya ; Miyashita, Kazuya ; Hirano, Takashi ; Kitada, Nobuo ; Takechi, Azusa ; Yagi, Takuya ; Yoshida, Chihiro ; Nakata, Chihiro ; Hara, Takahiko ; Maki, Shojiro A

To develop novel drugs for treating T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) which are highly malignant hematological tumors, a series of analogs having a polyenylpyrrole structure of natural compounds (rumbrin and auxarconjugatin B) were synthesized and investigated their structure-activity relationships (SAR) of in vitro anti-T-ALL and anti-AML activities. We obtained three findings: (1) introduction of a methyl group at the conjugated polyene terminus enhanced anti-T-ALL activity, (2) analogs with a 3-chloropyrrole moiety had even higher selectivity for T-ALL cells, and (3) some analogs were effective against AML-derived cells. Among the studied compounds, 3-chloro-2-(8-ethoxycarbonylnona-1,3,5,7-tetraenyl) pyrrole 4e was the most promising candidate of T-ALL- and AML-treating drug. This study provides useful structural information for designing novel drugs treating T-ALL and AML.

01 Apr 2021·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Synthesis of polyenylpyrrole derivatives with selective growth inhibitory activity against T-cell acute lymphoblastic leukemia cells

Q4 · MEDICINE

Article

Author: Hara, Takahiko ; Yagi, Takuya ; Hirano, Takashi ; Maki, Shojiro A ; Takechi, Azusa ; Nakata, Chihiro ; Higashi, Tomoya ; Saito, Ryohei ; Fujita, Yuki ; Obata, Rika ; Hachiro, Yoshifumi ; Kitada, Nobuo ; Miyashita, Kazuya ; Yoshida, Chihiro

T-cell acute lymphoblastic leukemia (T-ALL) is a hardly curable disease with a high relapse rate. 20 analogs were synthesized based on the structures of two kinds of fungi-derived polyenylpyrrole products (rumbrin (1) and auxarconjugatin-B (2)) to suppress the growth of T-ALL-derived cell line CCRF-CEM and tested for growth-inhibiting activity. The octatetraenylpyrrole analog gave an IC₅₀ of 0.27 μM in CCRF-CEM cells, while it did not affect Burkitt lymphoma-derived cell line Raji and the cervical cancer cell line HeLa, or the oral cancer cell line HSC-3 (IC₅₀ > 10 μM). This compound will be a promising compound for developing T-ALL-specific drugs.

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