Bioorganic & Medicinal Chemistry Letters 18 (2008) 1474–1477
Novel echinocandin antifungals. Part 1: Novel side-chain analogs
of the natural product FR901379
Masaki Tomishima,a,* Hidenori Ohki,a Akira Yamada,a
Katsuyuki Makib and Fumiaki Ikedab
aMedicinal Chemistry Research Laboratories, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan
bMedicinal Biology Research Laboratories, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan
Received 11 September 2007; revised 20 December 2007; accepted 22 December 2007
Available online 28 December 2007
Abstract—A series of novel acylated analogs of the novel water-soluble echinocandin FR901379 have been prepared and evaluated
for antifungal and hemolytic activity. A relationship between antifungal activity and lipophilicity of the acyl side chain, expressed as
ClogP was demonstrated, and an analog (3c) with 5.5- to 8-fold superior in vivo activity relative to the previously disclosed
4-(n-octyloxy)benzoyl side chain analog, FR131535 obtained.
Ó 2008 Elsevier Ltd. All rights reserved.
Fungal diseases in humans are serious in immunocom-
promised individuals who are susceptible to many
opportunistic systemic mycoses.1 An inability of the
host immune response to fight off attack from normally
benign environmental fungal pathogens leads to an in-
crease in the incidence of deep-seated, disseminated
mycoses.2 Difficulty in diagnosis of fungal infections
and delays in initiation of treatment are important fac-
tors in morbidity and mortality, however, drugs for
effective treatment are also in short supply. A large effort
has been dedicated to the discovery of novel antifungal
agents that are safer and more efficacious than known
drugs, however the difficulty in obtaining a good safety
profile has meant that the number of available drugs is
still actually quite small. Available drugs include the
polyene natural product amphotericin B and various li-
pid formulations, azole compounds such as fluconazole
and voriconazole, and the recently introduced candins.3
We have already reported the discovery and chemical
modification of several unique antifungal natural prod-
ucts that express antifungal activity by inhibition of the
synthesis of 1,3-b-glucan, including FR901379, the first
natural echinocandin with outstanding intrinsic water
solubility due to the presence of sulfonate moiety on the
hexapeptide nucleus.5,6 This natural product displayed
good antifungal activity, but had problems with hemoly-
sis and relatively weak activity against certain molds, e.g.
Aspergillus fumigatus. In earlier work reported by our
group, the analog FR131535 (2), a novel water soluble
echinocandin-like lipopeptide, was obtained from
FR901379 through a semi-synthetic sequence involving
microbial deacylation and chemical reacylation with an
octyloxybenzoyl side chain.7 This derivative showed po-
tent activities against C. albicans, A. fumigatus, and
P. carinii, comparable to the natural product, but showed
the major advantage of dramatically reduced hemolytic
activity compared to FR901379. The activity was compa-
rable, but not superior to fluconazole against C. albicans
infection in a murine infection model, hence further opti-
mization of activity was required.
Our research in this area started with a search for anti-
fungal natural products.4 In particular, we focused on
1,3-b-glucan synthesis as an attractive target, since this
polysaccharide is a primary component of the fungal cell
wall, a structure with no counterpart in mammalian cells.
These early efforts clearly established that semi-synthetic
modification of FR901379 could lead to improved anti-
fungal activity, especially against A. fumigatus, whilst at
the same time, reducing the hemolytic potential associ-
ated with the lipophilic palmitoyl side chain and
maintaining the excellent water-solubility, a feature crit-
ical for development of a parenteral formulation.
Keywords: Antifungal; Natural product; FR901379; FR13153; Echi-
nocandin; Candida albicans; Aspergillus fumigatus.
*
Corresponding author. Tel.: +81
6
6390 1285; e-mail:
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.12.062