Hoshinolactam, A new antitrypanosomal lactam

Abstract Image
Tropical diseases caused by parasitic protozoa are a threat to human health, mainly in developing countries. Trypanosomiasis (Chagas disease and sleeping sickness) and leishmaniasis, inter alia, are classified as neglected tropical diseases, and over 400 million people are at risk of contracting these diseases.

In addition, a parasite of the Trypanosoma genus, Trypanosoma brucei brucei, is the causative agent of Nagana disease in wild and domestic animals, and this disease is a major obstacle to the economic development of affected rural areas.

Although some therapeutic agents for these diseases exist, they have limitations, such as serious side effects and the emergence of drug resistance. Thus, new and more effective antiprotozoal medicines are needed

Marine natural products have recently been considered to be good sources for drug leads. In particular, secondary metabolites produced by marine cyanobacteria have unique structures and versatile biological activities, and some of these compounds show antiprotozoal activities. For example, coibacin A isolated from cf. Oscillatoria sp. exhibited potent antileishmanial activity, and viridamide A isolated from Oscillatoria nigro-viridis showed antileishmanial and antitrypanosomal activities.

constituents of marine cyanobacteria and reported an antitrypanosomal cyclodepsipeptide, janadolide.

The marine cyanobacterium was collected at the coast near Hoshino, Okinawa.

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Okinawa
沖縄市
Uchinaa

City

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EARLIER MERCK TEAM HAD REPORTED

US 5348970

CAS 159153-15-8

MF C₂₀ H₃₃ N O₅

_{MW 367.48}

2-Pyrrolidinone, 3,4-dihydroxy-5-(hydroxymethyl)-3-[3-(2-nonylcyclopropyl)-1-oxo-2-propenyl]-, [3S-[3α,3[E(1S*,2S*)],4β,5α]]-

Antitrypanosomal

Marine cyanobacterium

Human fetal lung fibroblast MRC-5 cells

Majusculoic acid

Malyngamide A.

PAPER

http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.7b00047

Recently, we isolated a new antitrypanosomal lactam, hoshinolactam (1), from a marine cyanobacterium.Structurally, 1 contains a cyclopropane ring and a γ-lactam ring. So far, some metabolites possessing either a cyclopropane ring or a γ-lactam ring have been discovered from marine cyanobacteria, such as majusculoic acid and malyngamide A. To the best of our knowledge, on the other hand, hoshinolactam (1) is the first compound discovered in marine cyanobacteria that possesses both of these ring systems. In addition, we clarified that 1 exhibited potent antitrypanosomal activity without cytotoxicity against human fetal lung fibroblast MRC-5 cells. Here, we report the isolation, structure elucidation, first total synthesis, and preliminary biological characterization of hoshinolactam (1).

Isolation and Total Synthesis of Hoshinolactam, an Antitrypanosomal Lactam from a Marine Cyanobacterium

Hidetoshi Ogawa^†, Arihiro Iwasaki^†, Shimpei Sumimoto^†, Masato Iwatsuki^‡§, Aki Ishiyama^‡§, Rei Hokari^‡, Kazuhiko Otoguro^‡, Satoshi O̅mura^‡, and Kiyotake Suenaga ^*^†

^† Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan

^‡ Research Center for Tropical Diseases, Kitasato Institute for Life Sciences, and ^§Graduate School of Infection Control Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Org. Lett., Article ASAP

DOI: 10.1021/acs.orglett.7b00047

*E-mail: suenaga@chem.keio.ac.jp.

Abstract Image

In the search for new antiprotozoal substances, hoshinolactam, an antitrypanosomal lactam, was isolated from a marine cyanobacterium. The gross structure was elucidated by spectroscopic analyses, and the absolute configuration was determined by the first total synthesis. Hoshinolactam showed potent antitrypanosomal activity with an IC₅₀ value of 3.9 nM without cytotoxicity against human fetal lung fibroblast MRC-5 cells (IC₅₀ > 25 μM).

Table 1. ¹H and ¹³C NMR Data for 1 in C₆D₆

unit	position	δ_C^a	δ_H^b (J in Hz)
HIMP	1	177.8, C
	2	44.1, CH	2.51, dq (5.2, 7.6)
	3	80.8, CH	4.94, dd (4.6, 5.2)
	4	57.3, CH	3.49, ddd (4.6, 4.7, 9.4)
	5a	44.6, CH₂	1.21, m
	5b		1.36, m
	6	25.0, CH	1.61, m
	7	21.7, CH₃	0.74, d (6.2)
	8	23.2, CH₃	0.76, d (6.3)
	9	15.0, CH₃	1.33, d (7.6)
	NH		7.65, s
PCPA	1	166.0, C
	2	117.4, CH	5.88, d (15.5)
	3	155.0, CH	6.59, dd (10.3, 15.5)
	4	22.4, CH	0.91, m
	5	23.3, CH	0.59, m
	6	35.7, CH₂	0.96, m
	7	22.5, CH₂	1.20, tq (7.1, 7.3)
	8	14.0, CH₃	0.78, t (7.3)
	9a	16.1, CH₂	0.35, ddd (4.5, 6.0, 8.2)
	9b		0.42, ddd (4.5, 4.5, 8.8)

aMeasured at 100 MHz.

bMeasured at 400 MHz.

Positive HRESIMS data (m/z 308.2228, calcd for C₁₈H₃₀NO₃ [M + H]⁺ 308.2225). Table 1 shows the NMR data for 1.

An analysis of the ¹H NMR spectrum indicated the presence of four methyl groups (δ_H 0.74, 0.76, 0.78 and 1.33), four protons of the cyclopropane ring (δ_H 0.35, 0.42, 0.59 and 0.91), and two olefinic protons (δ_H 5.88 and 6.59).

The ¹³C NMR and HMQC spectra revealed the existence of two carbonyl groups (δ_C 166.0 and 177.8) and two sp² methines (δ_C 117.4 and 155.0).

Examination of the COSY and HMBC spectra established the presence of two fragments derived from 4-hydroxy-5-isobutyl-3-methylpyrrolidin-2-one (HIMP) and 3-(2-propylcyclopropyl) acrylic acid (PCPA), respectively. The configuration of the C-2–C-3 olefinic bond in the PCPA was determined to be trans on the basis of the coupling constant (³J_H2–H3 = 15.5 Hz). The connectivity of the two partial structures was determined from the HMBC correlation (H-3 of HIMP/C-1 of PCPA).

¹H, ¹³C, COSY, HMQC, HMBC, and NOESY NMR spectra in C₆D₆ and ¹H and ¹³C NMR spectra in CD₃OD for hoshinolactam (1)