Synthesis of 23,23-Difluoro-24-nor- and 24′,24′-Difluoro-24-Homovitamin D3 Analogues and Unexpected Structure-Activity Relationships
Fumihiro Kawagoe; Hiroya Tabuchi; Taiyo Ideguchi; Yuki Okamoto; Souma Murata; Tomofumi Yatsu; Syota Yamada; Kaori Yasuda; Yusuke Akagi; Masashi Takano; Toshie Fujishima; Yoshiki Miyata; Ken’ichi Aoki; Toshiyuki Sakaki; Atsushi Kittaka
Organics, 27 Apr. 2026, [Reviewed]
We synthesized two vitamin D3 analogues, 3 and 4, which have a shortened or elongated fluoro-side-chain based on 24,24-difluoro-25-hydroxyvitamin D3 (5) using an efficient convergent approach and studied their preliminary biological activity. Both analogues exhibited greater resistance to CYP24A1-mediated metabolism than the natural 25-hydroxyvitamin D3 (6), although their stability was lower than that of 5. Analogue 3 showed an approximately 100-fold lower human vitamin D receptor (hVDR)-binding affinity compared with 5 and 6. Despite this marked reduction in VDR-binding affinity, it demonstrated an approximately 1.5-fold increase in VDR-ligand binding domain (LBD) transcriptional activation of the natural ligand 6. In contrast, analogue 4 displayed moderate VDR-binding affinity and VDR-LBD transactivation compared with 5 and 6. We found that compound 3 is a unique vitamin D analogue with a fluorinated and shortened side-chain, exhibiting low binding affinity for hVDR but potent transcriptional activity through VDR-LBD with its long half-life; thus, 3 may serve as a basic structural skeleton for advancing medicinal chemistry and drug discovery.

C22- to C26,27-Fluoro-2-(3-hydroxypropyl)-19-norvitamin D3,side-chain fluorinated MART-10s suppress IL-19 secretion from Th17-stimulated keratinocytes: Potent therapeutic effects on psoriasis models
Fumihiro Kawagoe; Sayuri Mototani; Mana Yamaguchi; Akiko Takeuchi; Tomofumi Yatsu; Kaori Yasuda; Masashi Takano; Yusuke Akagi; Toshie Fujishima; Yoshiki Miyata; Hiroshi Saitoh; Toshiyuki Sakaki; Atsushi Kittaka
Synlett, 21 Apr. 2026, [Reviewed]
Psoriasis is a chronic inflammatory disorder characterized by skin inflammation and hyperproliferation due to abnormal differentiation of basal keratinocytes. The etiology is unclear, but psoriasis has been described as a prototypic Th17-mediated disease. Interleukin-19 (IL-19) is a component of the pathogenetic IL-23/IL-17 cascade in psoriasis, and IL-19 production is induced in keratinocytes by IL-17A. However, the therapeutic applications of IL-19 for human disease have yet to be developed. We synthesized 24 new kinds of side-chain fluorinated 2-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 analogues based on the MART-10 and MART-11 skeletons, and their suppressive effects on keratinocyte IL-19 secretion were assessed. Surprisingly, more than half of the analogues exhibited potent suppressive effects with much greater efficiency than calcipotriol, a commonly clinically used medicine for the treatment of psoriasis. Furthermore, one of the best analogues, 24F2-MART-10, was selected to study therapeutic effects on psoriasis model mice. We found that comparable efficacy was achieved using only one-fifth of the volume of calcipotriol, highlighting the superior therapeutic potency of 24F2-MART-10. Osteocalcin promoter transactivation activity of all 24 analogues was also tested.

Comprehensive Synthesis of Side-Chain Fluorinated 2α-[2-(Tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 Analogs and Preliminary Biological Activities
Fumihiro Kawagoe; Sayuri Mototani; Yuki Okamoto; Souma Murata; Akiko Takeuchi; Tomofumi Yatsu; Kaori Yasuda; Yusuke Akagi; Toshie Fujishima; Yoshiki Miyata; Hiroshi Saitoh; Toshiyuki Sakaki; Atsushi Kittaka
Chemical and Pharmaceutical Bulletin, 30 Jan. 2026, [Reviewed]

Side-Chain Fluorine Engineering of Vitamin D3 Derivatives for VDR-Silent SREBP Inhibitors
Fumihiro Kawagoe; Sayuri Mototani; Tomofumi Yatsu; Yasushi Takemoto; Yusuke Akagi; Toshie Fujishima; Yoshiki Miyata; Motonari Uesugi; Atsushi Kittaka
Chemical and Pharmaceutical Bulletin, 20 Sep. 2025, [Reviewed]

Synthesis and in Vitro Cytotoxicity Evaluation of Jadomycins
Erika Iwasaki; Yoshimi Shimizu; Yusuke Akagi; Toshiya Komatsu
Chemical and Pharmaceutical Bulletin, 01 Sep. 2023, [Reviewed]
Jadomycins, which are benzo[b]phenanthridine-type alkaloids isolated from Streptomyces venezuelae ISP5230, exhibit cytotoxic activity against multidrug-resistant breast cancer cells. We have previously achieved the total synthesis of jadomycins using the direct arylation of juglone as a key step. In this study, we achieved the total synthesis of jadomycin T and jadomycin aglycons using L-threonine and 1-amino-2-propanol as nitrogen sources. Additionally, we evaluated the cytotoxic activity of eight compounds, including glycosides, jadomycin T, and their corresponding aglycons, in eight types of tumor cells. The evaluated jadomycins tended to exhibit stronger cytotoxic activity as aglycons than as glycosides. Although the presence of a 1,3-oxazolidine ring derived from an amino acid was not essential, the presence of the 1,3-oxazolidine ring showed strong activity when the ring had a carboxyl group. Furthermore, compared to the non-natural isomer at a different position on the phenolic hydroxyl group, the naturally occurring phenanthroviridin aglycon exhibited stronger cytotoxic activity. In addition, this study suggests that jadomycins may become lead compounds for the treatment of brain tumors; however, further studies on their ability to penetrate the blood-brain barrier are required.

Total synthesis of jadomycins A, B, and l-digitoxosyl-phenanthroviridin
Yusuke Akagi; Yuta Mori; Yudai Sato; Erika Iwasaki; Toshiya Komatsu
Tetrahedron Letters, Jul. 2022, [Reviewed]

Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo
Fumihiro Kawagoe; Aileen Mendoza; Yuki Hayata; Lisa Asano; Kenjiro Kotake; Sayuri Mototani; Satoshi Kawamura; Shigeyuki Kurosaki; Yusuke Akagi; Yasushi Takemoto; Kazuo Nagasawa; Hayato Nakagawa; Motonari Uesugi; Atsushi Kittaka
Journal of Medicinal Chemistry, 13 May 2021, [Reviewed]

Total Synthesis of Phenanthroviridin Aglycon and Its Analog
Yusuke Akagi; Kohei Harasawa; Toshiya Komatsu
Asian Journal of Organic Chemistry, May 2021, [Reviewed]

Palladium-catalyzed arylation of 1,4-naphthoquinones with aryl iodides and its synthetic application to the benzo[b]phenanthridine skeleton
Akagi, Y.; Komatsu, T.
Tetrahedron Letters, 2020, [Reviewed]

Palladium-Catalyzed β-Arylation of Cyclic α,β-Unsaturated O-Methyl Oximes with Aryl Iodides
Akagi, Y.; Fukuyama, S.; Komatsu, T.
Chemical & pharmaceutical bulletin, 2020, [Reviewed]

Synthetic Chemical Probes That Dissect Vitamin D Activities
Nagata, A.; Akagi, Y.; Asano, L.; Kotake, K.; Kawagoe, F.; Mendoza, A.; Masoud, S.S.; Usuda, K.; Yasui, K.; Takemoto, Y.; Kittaka, A.; Nagasawa, K.; Uesugi, M.
ACS Chemical Biology, 2019, [Reviewed]

Stereoselective Synthesis of Four Calcitriol Lactone Diastereomers at C23 and C25
Nagata, A.; Akagi, Y.; Masoud, S.S.; Yamanaka, M.; Kittaka, A.; Uesugi, M.; Odagi, M.; Nagasawa, K.
Journal of Organic Chemistry, 2019, [Reviewed]

Synthetic studies of (23S,25R)-1α,25-dihydroxyvitamin D3 26,23-lactone (calcitriol lactone) and its derivatives
Akagi, Y.; Nagata, A.; Odagi, M.; Nagasawa, K.
Journal of Steroid Biochemistry and Molecular Biology, 2018, [Reviewed]

A-Ring Synthons of 19-Nor Type Vitamin D Derivatives
Akagi, Y.; Yasui, K.; Nagasawa, K.
Journal of Steroid Biochemistry and Molecular Biology, 2017, [Reviewed]

Synthesis of diastereomers of 1,3-cis-25-dihydroxy-19-norvitamin D3
Usuda, K.; Biswas, T.; Yamaguchi, T.; Akagi, Y.; Yasui, K.; Uesugi, M.; Shimizu, I.; Hosokawa, S.; Nagasawa, K.
Chemical and Pharmaceutical Bulletin, 2016, [Reviewed]

Synthesis of 24,24-difluoro-1,3-cis-25-dihydroxy-19-norvitamin D3 derivatives and evaluation of their vitamin D receptor-binding affinity
Biswas, T.; Akagi, Y.; Usuda, K.; Yasui, K.; Shimizu, I.; Okamoto, M.; Uesugi, M.; Hosokawa, S.; Nagasawa, K.
Biological and Pharmaceutical Bulletin, 2016, [Reviewed]

Synthesis of 1 α- and 1 β-amino-25-hydroxyvitamin D3
Akagi, Y.; Usuda, K.; Tanami, T.; Yasui, K.; Asano, L.; Uesugi, M.; Nagasawa, K.
Asian Journal of Organic Chemistry, 2016, [Reviewed]

Synthesis of jadomycin A and related jadomycin aglycons: Structural re-examination of jadomycins S and T may be needed
Tajima, T.; Akagi, Y.; Kumamoto, T.; Suzuki, N.; Ishikawa, T.
Tetrahedron Letters, 2012, [Reviewed]

Synthetic studies on jadomycins: synthesis of dimethyljadomycin A
Akagi, Y.; Yamada, S.-i.; Etomi, N.; Kumamoto, T.; Nakanishi, W.; Ishikawa, T.
Tetrahedron Letters, 2010, [Reviewed]

天然物合成を指向したナフトキノンの位置選択的なアリール化反応の開発とその応用
01 Apr. 2025 - 31 Mar. 2028