646 CHIMIA 2017, 71, No.

10 Medicinal cheMistry
doi:10.2533/chimia.2017.646 Chimia 71 (2017) 646–652 © Swiss Chemical Society

Drugs from the Oceans: Marine Natural

Products as Leads for Drug Discovery
Karl-Heinz Altmann*

Abstract: The marine environment harbors a vast number of species that are the source of a wide array of struc-
turally diverse bioactive secondary metabolites. At this point in time, roughly 27’000 marine natural products
are known, of which eight are (were) at the origin of seven marketed drugs, mostly for the treatment of cancer.
The majority of these drugs and also of drug candidates currently undergoing clinical evaluation (excluding anti-
body–drug conjugates) are unmodified natural products, but synthetic chemistry has played a central role in the
discovery and/or development of all but one of the approved marine-derived drugs. More than 1000 new marine
natural products have been isolated per year over the last decade, but the pool of new and unique structures is far
from exhausted. To fully leverage the potential offered by the structural diversity of marine-produced secondary
metabolites for drug discovery will require their broad assessment for different bioactivities and the productive
interplay between new fermentation technologies, synthetic organic chemistry, and medicinal chemistry, in order
to secure compound supply and enable lead optimization.
Keywords: Clinical development · Drug discovery · Marine natural products · Marine organisms · Medicinal
chemistry · Organic synthesis · Semisynthesis

1. Introduction important current target for new anticancer Porifera (sponges) and Cnidaria being the
drugs or the discovery of S1P receptors as most dominant sources by far (accounting
Natural products (NPs) have played a a new target family for drug discovery in for ca. 57% of the total number of bioac-
central role in drug discovery and develop- different disease areas (based on mecha- tive marine NPs).[11] These organisms are
ment ever since the first isolation of a NP nistic studies with the NP rapamycin[4] and not equipped with any physical means of
in pure form, i.e. morphine from opium by the NP-derivative FTY720 (fingolimod),[5] protection;[12] instead, they release second-
Serthürner in 1805. While the exact num- respectively). The possible reasons for the ary metabolites, e.g. toxins,[13] as a chemi-
bers vary depending on the type of analysis pronounced lead potential of NPs for drug cal way of defense.[14] It should be noted,
(including the definition of the term natu- discovery have been discussed in a number however, that many of these compounds
ral product), it is indisputable that NPs are of recent review articles[6] and they shall are not produced by the apparent source
at the origin of a large fraction of our cur- not be reiterated here. organism itself, but rather originate from
rent armamentarium of drug molecules, While the majority of NP-derived drugs or are made in concert with single-celled
either as such (i.e. as unmodified NPs) or originate from terrestrial plants, fungi, or organisms (dinoflagellates, bacteria, and
as lead structures for drug discovery and microorganisms, NPs isolated from marine others), many of which have not been cul-
development.[1–3] In a more indirect way, organisms are assuming an ever increasing tured. Thus, the total biomass of a sponge
NPs or (semi)synthetic NP-derivatives can role in the search for new bioactive second- may include up to 35% of bacterial cells[15]
also serve as probes for chemical biology ary metabolites. A priori, this is not a sur- and more than 25 bacterial phyla have been
studies, which may then provide new input prising development as oceans cover 70% isolated from marine sponges.[16] It has
for drug discovery; prominent examples of of the earth’s surface and represent 95% of also been noted that 22% of the 411 NPs
this type are the emergence of mTOR as an its biosphere;[7] it has been estimated that known in 2013 to be produced by marine
the marine environment harbors more than actinomycetes were derived from sponge-
one million species and is home to one bil- associated species.[17]
lion different kinds of marine microbes.[8] A broad range of biological effects has
The species diversity offered by the marine been described for marine NPs, but the
environment can be expected to translate spectrum is clearly dominated by cytotoxic
into structural diversity at the level of the and antiproliferative activities (>50% of all
secondary metabolites produced.[9] In fact, bioactivities reported).[11] While this may
it has been argued that compared to their indeed reflect the natural function of these
terrestrial counterparts, marine NPs show compounds as part of the chemical defense
a higher incidence of significant bioactiv- machinery of the producing organism (or
ity, which is often associated with a high the host organism harboring the producing
degree of structural novelty.[9,10] species), it may also be caused by a bias
Out of the 35 known phyla of the ani- in the profiling of marine NPs, which is
*Correspondence: Prof. Dr. K.-H. Altmann
ETH Zürich
mal kingdom, 34 are represented in the ma- often limited to the assessment of effects
Department of Chemistry and Applied Biosciences rine environment, with 8 being exclusively on cancer cell proliferation/survival.
Institute of Pharmaceutical Sciences aquatic.[7] Thus, the majority of bioactive The number of newly isolated marine
Vladimir-Prelog-Wag 4 marine natural products have been iso- NPs is steadily increasing and significantly
HCI H 405
CH-8093 Zurich lated from invertebrates (75% during the more than 1000 new compounds per year
E-mail: karl-heinz.altmann@pharma.ethz.ch period from 1985 to 2012), with the phyla have been isolated regularly since 2008,[18]
Medicinal cheMistry CHIMIA 2017, 71, No. 10 647

bringing the total number of marine natu- chemical synthesis not only allows access bine (ara-C, arabinosylcytosine) and the
ral products to ca. 27’000 by the end of to the natural product itself, but it also of- antiviral agent vidarabine (ara-A, arabi-
2015.[19] This increase is fueled by a tre- fers the potential to deliver structures not nosyladenine) (Fig. 1). As has been dis-
mendous number of new marine species easily accessible by derivatization or mod- cussed elsewhere,[27] there is a direct line
that are discovered every year, with ad- ification of an isolated natural product.[10] of chemical research that links these drugs
vances in diving and submersibles tech- At this point in time, seven (types of) to the sponge natural products spongothy-
nology enabling sample collections in drugs have been approved for clinical use midine and spongouridine. Cytarabine was
previously difficult-to-access regions. At that can be confidently traced back to a FDA-approved in 1969 and is still in use
the same time, the increased efficiency of marine NP (for the purpose of this review, today for the treatment of acute lympho-
genome sequencing provides information the three FDA-approved products that are cytic leukemia (ALL), acute myeloid leu-
on an ever growing number of biosynthetic based on ω3 polyunsaturated fatty acids kemia (AML), non-Hodgkins lymphoma,
gene clusters,[20] and improved spectro- will be considered as one ‘drug’) and sev- and myelodysplastic syndrome (MDS);
scopic methods allow for structure eluci- eral more are at various stages of clinical vidarabine was approved in 1976 for the
dation with trace amounts of unknown sub- development. This short review in a first treatment of Herpes infections, but is no
stances.[21] Notwithstanding these recent part summarizes the origin, structure, and longer in use either in the US or in Europe.
advances, the set of organisms that have clinical uses of the marine-derived drugs The first FDA-approved drug that was
been scrutinized for bioactive secondary that are approved at this point in time and directly derived from a marine NP was the
metabolites is still very limited and much it attempts to highlight some of the key as- pain medication ziconotide in 2004 (as
remains to be discovered.[18] pects of their discovery and development. Prialt®). Ziconotide is the synthetic equiv-
The intriguing and often unique biolog- In a second part, individual candidate alent (manufactured by chemical synthe-
ical profiles of marine secondary metabo- drugs that are currently undergoing clinical sis but structurally identical with) of the
lites should make them attractive starting development will be discussed. Lastly, a peptide toxin ω-conotoxin MVIIA, which
points for drug discovery, but marine NP- short perspective will be provided on SAR comprises 25 amino acid residues and in-
based biomedical research is faced with a studies on complex marine NPs and the cludes three disulfide bonds (Fig. 2).[28]
number of intrinsic obstacles that do not future of marine NP-based drug discovery. ω-conotoxin MVIIA is produced by the
exist for terrestrial NPs (or at least not to venomous fish-hunting cone snail Conum
the same extent). While adequate material magnus as a component of a whole collec-
supply for pharmacological profiling and 2. Marine NP-derived Drugs tion of toxins that serve to immobilize prey
eventual drug development can be a prob- by targeting different physiological mecha-
lem for both marine as well as terrestrial The first marine NPs with a clear im- nisms in their neuromuscular system.[28] It
NPs, in general, this issue is significantly pact on the development of drugs for hu- is a highly specific antagonist of the N-type
more pronounced for marine-derived com- man use, if only indirectly, were the ara- voltage-gated calcium channel Cav2.2,[29]
pounds. In many cases, the latter are ini- bino-nucleosides spongothymidine and thus blocking excitatory neurotransmitter
tially obtained from the natural source in spongouridine (Fig. 1) that were isolated release from the primary afferent nerve
very low quantities and compound supply in the early 1950s by Bergman and Feeney terminals, which results in antinociception.
often cannot be sustained for ecological from extracts of the sponge Tectitethya Ziconotide is indicated for the management
(and also economic reasons).[22] For marine crypta.[24,25] Interestingly, it has never been of severe and chronic pain in patients who
bacteria, this hurdle has been overcome determined if these compounds are in fact are refractory or intolerant to other pain
by large-scale fermentation in individual produced by the sponge itself or by as- medications, including opioid analgesics;
cases, but this required substantial opti- sociated microorganisms, although it was the drug needs to be administered by intra-
mization of fermentation conditions (vide recently shown that other nucleosides that thecal infusion, which limits the breadth of
infra).[10] On the other hand, more deli- are found in extracts of Tectitethya crypta its application. However, it has been point-
cate organisms like sponges, are difficult are of bacterial origin.[26] ed out[30] that apart from its use as a power-
to cultivate;[13] in addition, relevant gene The discovery of spongothymidine and ful analgesic, the value of ziconotide is also
clusters may remain silent under breeding spongouridine spurred the synthesis and manifest in the identification of Cav2.2 as a
conditions, although this has been resolved biological evaluation of numerous other target for pain suppression, which can now
by mixed fermentation, in some cases.[10] nucleosides, eventually leading to the dis- be pursued with small molecules that may
Apart from biotechnological approaches, covery of the anti-leukemia drug cytara- be orally bioavailable.
the total chemical synthesis of marine NPs
in many cases has proven to be a suitable Fig. 1. Molecular
means to generate material for biological O H
N
O
O
N
NH2 structures of the ma-
N
interrogation, at least at an early stage of O N O N O
N NH2 rine NPs spongouri-
HO HO HO
biomedical research.[23] Moreover, while R
N N dine and spongo-
HO OH HO OH HO OH
synthetic routes to elaborate carbon scaf- thymidine and of the
folds and/or complex stereochemical ar- Spongouridine: R = H
Spongothymidine: R = Me
ara-C ara-A derived drugs ara-C
rays often take a long time to establish, and ara-A.

S S

S S

H-CYS-LYS-GLY-LYS-GLY-ALA-LYS-CYS-SER-ARG-LEU-MET-TYR-ASP-CYS-CYS-THR-GLY-SER-CYS-ARG-SER-GLY-LYS-CYS-NH2

S S

Fig. 2. Amino acid sequence of ω-conotoxin MVIIA (ziconotide) and arrangement of disulfide bonds.
648 CHIMIA 2017, 71, No. 10 Medicinal cheMistry

Like ziconotide, the anticancer drug as part of their total synthesis of ET-743.[35] drin B by a CH2 group in eribulin (i.e. the
trabectedin embodies the structure of a NP, According to ref. [34], trabectedin is ob- transformation of a macrolactone into a
in this case the alkaloid ET-743 (Scheme tained from cyanosafracin B in 23 steps macroketone) being triggered by the insuf-
1). The latter is a member of a larger family and 3% overall yield. ficient metabolic stability of E2 in mouse
of related structures that were first isolated The complexity of the process for the serum.[36] Eribulin is produced in 62 chem-
from the Caribbean tunicate Ecteinascidia production of trabectedin is even surpassed ical steps from commercial starting mate-
turbinata in 1990 by Rinehart and co- by the chemistry associated with the prepa- rials; a Nozaki-Hiyama-Kishi reaction
workers and termed ecteinascidins;[31] ration of eribulin, which is a fully synthetic at C13–C14 constitutes the ring-closing
ET-743 was simultaneously also isolated truncated derivative of the marine natural step.[36] Eribulin mesylate was approved
by Wright and co-workers from the same product halichondrin B (Scheme 2).[36] by the FDA in 2010 (as Halaven®) for the
organism.[32] The latter was isolated in 1986 by Hirata treatment of metastatic breast cancer in pa-
The compound covalently modifies and Uemura from the marine sponge tients who previously received at least two
DNA by preferential binding to GC-triplets Halichondria okadai (together with a chemotherapeutic regimens. While it is not
and subsequent reaction with the guanine number of related structures) and found to known to this author how much material is
amino group at the carbinolamine site, exhibit highly potent antitumor activity.[37] manufactured to meet the clinical demand
ultimately causing double strand breaks Halichondrin B was subsequently demon- of eribulin, the amount probably does not
through engagement of the Nucleotide strated to be a tubulin polymerization in- exceed a few kg per year.
Excision Repair (NER) system.[33] hibitor and it has generally been assumed Notwithstanding the awesome com-
Trabectedin has been approved in Europe that binding of the compound to tubulin plexity of eribulin, the structurally most
since 2007 (asYondelis®), for the treatment occurs at the vinca site.[38] However, while complex marine-derived drug is arguably
of soft tissue sarcoma and ovarian cancer; no structural data are available for tubulin- the anticancer drug brentuximab-vedotin.
the compound also obtained FDA approval bound halichondrin B, it has recently been Brentuximab-vedotin is an antibody-drug
in 2015 as second line treatment of meta- shown that eribulin binds to a new site on conjugate (ADC) that is composed of an
static liposarcoma or leiomyosarcoma. β-tubulin that does not overlap with the antibody against the tumor-specific surface
In contrast to ziconotide, the natural vinca domain.[39] antigen CD30, a cathepsin B-cleavable
source organism in the case of trabectedin The discovery of eribulin has its ori- linker moiety (to allow for preferential
did not yield sufficient quantities of the gin in the work of Kishi and colleagues drug release in tumor cells) and the penta-
drug substance in an economically viable on the total synthesis of halichondrin B peptide monomethyl auristatin E as a cyto-
process, although aquaculture was used and related natural products.[40] Biological toxic drug cargo (Fig. 3).[41] Monomethyl
to produce material for part of the clini- evaluation of the halichondrin fragments auristatin E is a synthetic analog of the
cal studies.[34] The supply problem for tra- generated as part of the total synthesis marine natural product dolastatin 10 (Fig.
bectedin was ultimately overcome by the work revealed that the biological activity 3);[42] the latter was isolated by Pettit and
development of a semisynthesis route from of halichondrin B was almost exclusively co-workers from the sea hare Dolabella
another natural product, cyanosafracin B, associated with the macrocyclic part of the auricularia and found to be an extremely
that can be obtained by fermentation of the structure (E1) (Scheme 2).[36] However, potent cytotoxic and antitumor agent.[43]
bacterium Pseudomonas fluorescens.[34] while truncated analog E1 was highly po- Monomethyl auristatin E together with
One of the key steps in this semisynthesis tent in vitro, it showed no in vivo antitumor a series of related analogs was first pre-
is the conversion of T1 into T3 via quinone activity. This finding spurred further syn- pared by the Pettit group as part of a more
methide T2 in 58% overall yield (Scheme thetic work that led to analog E2 and even- comprehensive SAR study around dolas-
1), using conditions that had been devel- tually to eribulin, with the replacement of tatin 10[42] and later found to be an ideal
oped previously by Corey and co-workers the bridging lactone oxygen in halichon- cargo for ADCs.[41] Like halichondrin B
and eribulin, dolastatin 10 and auristatin
E (and also F, vide infra) are inhibitors of
OMe
HO
tubulin assembly. However, in contrast to
HO Me
O NH OMe
eribulin, auristatin E has been shown in
H
Me
N Me
MeO
O HO Me structural studies to bind to the vinca do-
MeO
N AcO S
O H main on tubulin[44] (as is also the case for
Me
O
NH
CN N Me dolastatin 10, based on biochemical stud-
N
NH2 O ies[45]). Brentuximab vedotin was approved
O
Me
O OH
by the FDA in 2011 (as Adcetris®) for the
Cyanosafracin B Trabectedin (ET-743) treatment of patients with Hodgkin lym-
phoma (after failure of autologous stem
cell transplant (ASCT) or after failure of at
least two prior multi-agent chemotherapy
OMe OMe regimens if patients are not ASCT candi-
Me Me
O
MOMO
O
MOMO
TrocHN H MOM OMe dates) or with systemic anaplastic large
O Me
Me
OH H
N Me a)-c)
Me
H
N Me d), e)
O
AcO S
cell lymphoma (after failure of at least
N N Me
O H
N Me
one prior multi-agent chemotherapy regi-
O O
O CN O CN N men). In Europe the drug was approved in
O O O
O OH 2015.
O SFm O SH
NHTroc NHTroc A special type of marine NP-derived
T1 T2 T3 drugs are ω3 polyunsaturated fatty acids,
Troc = trichloroethoxycarbonyl; Fm = 9-fluorenylmethyl in the sense that they have much simpler
structures than all of the other compounds
Scheme 1. Molecular structure of trabectedin and one of the key transformations in its semisyn- discussed in this section. In 2004, the FDA
thesis from cyanosafracin B. a) DMSO, Tf2O, CH2Cl2, –40 °C; b) i-Pr2NEt, 0 °C; c) t-BuOH, 0 °C; d) approved a mixture of the ethyl esters of
((CH3)2N)2C=N-t-Bu; e) Ac2O, 23 °C, 58%. fish-derived ω3 polyunsaturated fatty ac-
Medicinal cheMistry CHIMIA 2017, 71, No. 10 649

2014, respectively, for the same indication

H
O
H
O
H
O
MeO as Lovaza®.
H
HO O H H
O O O O O O
HO O O O O
H H H H H H OH H H H
H O H2N
H
HO O O
O
O
O O
O
O
3. Marine NP and NP Derivatives in
O O
14 13 Clinical Development
Halichondrin B Eribulin
It is obviously difficult to assemble a
reliable collection of all marine-derived
drug candidates currently undergoing
clinical development, as this information
H H
is fragmented across the literature or may
HO O O
H
HO
O O
H
not at all be in the public domain. The fol-
HO
H
O
H
O O
H
O
H
HO
H
O
H
O O
H
O
H
lowing discussion is based on the infor-
O O O O mation available on the website ‘Marine
O O
O O Pharmacology’[47] that is maintained by
O O
Prof. A. M. S. Meyer, who is a professor of
E1 E2
pharmacology at Midwestern University in
Chicago, IL, USA. According to this web-
Scheme 2. Molecular structures of halichondrin B and eribulin and of two crucial analog struc- site, 27 marine-derived drug candidates
tures on the discovery path from NP to synthetic drug. were in clinical development in April 2016;
for one of these compounds, ADC ABV-
833, development has been terminated in
the meantime. While this (corrected) num-
ber may not be fully accurate at this point
A -C
in time, at least 26 compounds appear to
be undergoing active development or stud-
ies are planned (5 in Phase III, 8 in Phase
II, and 13 in Phase I). Interestingly, 23 of
these 26 compounds are developed for on-
cology indications and of those 23, 17 are
ADCs that are based on two marine NP-
derivatives only (monomethyl auristatin E
(13 ADCs) and monomethyl auristatin F
(4, Fig. 3)). Thus, the structural diversity
of the clinical pipeline is more limited than
the plain numbers seem to suggest. Of the
low-molecular weight compounds, all but
two are unmodified NPs (exceptions are
the Phase II compounds lurbinectedin,[48]
which is an analog of trabectedin, and
GTS-21,[49] which is a synthetic derivative
Fig. 3. Molecular structures of the ADC brentuximab vedotin, the natural product dolastatin 10
and the derived synthetic antimitotic agents auristatin E, monomethyl auristatin E, and mono-
of anabaseine) and the majority is prepared
methyl auristatin F. by chemical synthesis (based on publicly
available information).
It is not the purpose of this review to
address each of these drug candidates ex-
ids (Lovaza®), primarily eicosapentaenoic glycerol acyltransferase, increased mito-
plicitly, rather only three specific examples
acid (EPA) and docosahexaenoic acid chondrial and peroxisomal β-oxidation in
shall be highlighted in the following, each
(DHA) (Fig. 4), as an adjunct to diet to the liver, and increased plasma lipoprotein
of which is distinct by its structure or mode
reduce triglyceride levels in patients with lipase activity.[46] In addition, EPA and
of action (or both).
severe hypertriglyceridemia. DHA are poor substrates for the enzymes
Lovaza® is derived from fish oil ob- responsible for triglyceride synthesis and
3.1 Tetrodotoxin
tained from ocean fish families such as they inhibit esterification of other fatty ac-
Tetrodotoxin (TTX) is a marine alka-
Engaulidae, Carangidae, Clupeidae, ids. In the meantime, pure EPA ethyl ester
loid with a unique pentacyclic structure
Osmeridae, Salmonidae, and Scromboidae. (Vascepa®) and a mixture of free (fish-de-
(Fig. 5). The compound is well known as
The mechanism of action of the drug is not rived) ω3 polyunsaturated acids, consist-
the (highly) toxic principle of the puffer-
completely understood, but is likely to in- ing primarily of EPA and DHA (Epanova®)
fish (which is considered a culinary spe-
clude inhibition of acyl-CoA:1,2-diacyl- have been FDA-approved in 2013 and
cialty in Japan, but also in other countries).
However, TTX is not unique to pufferfish,
but has been isolated from at least six phyla
Fig. 4. The major fish- of organisms within the Animalia king-
O O derived ω3 polyunsat- dom, thus suggesting that the compound
OH OH urated fatty acids. may actually be produced by symbiotic
bacteria (including TTX in pufferfish).[50]
Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA) The compound is an antagonist of volt-
age-gated sodium channels and its analge-
650 CHIMIA 2017, 71, No. 10 Medicinal cheMistry

ery of new molecular architectures and bio- to be compared to the total number of
activities (vide supra). Salinosporamide A marine NPs known, which is on the order
O is a potent inhibitor of the 20S proteasome of 27’000.[19] Even if one excludes spon-
OH from different species, including humans, gothymidine and spongouridine from the
O OH NH2 and thus acts on the same molecular tar- analysis (in light of their only indirect im-
O H
N get as the approved anticancer drugs bort- pact on the discovery of ara-C and ara-A),
HO N ezomib and carfilzomib.[60] Proteasome the discovery of five drugs from a pool of
HO H inhibition by salinosporamide A is based only 27’000 compounds is highly impres-
OH
on a unique mechanism that first involves sive and certainly exceeds the success rates
lactone opening by the side chain hydroxy of HTS-based drug discovery. At the same
Fig. 5. Three-dimensional structure of the
group of the active site Thr, followed by time, it is also true that with the exception
marine toxin tetrodotoxin.
intramolecular displacement of chloride of ω3 polyunsaturated fatty acids all of the
by the hydroxy group released from the marketed drugs (and also candidate drugs)
lactone ring, to form a tetrahydrofuran are derived either from a (cyto)toxic (the
sic effects are related to the inhibition of ring (Fig. 7). Salinosporamide A has com- majority) or a neurotoxic NP. It has been
the initiation and conduction of impulses pleted a number of Phase I studies and is suggested that the past focus of marine
in the peripheral nervous system.[51] TTX currently undergoing another Phase I and NP-based drug discovery on oncological
is currently undergoing Phase III clinical a Phase I/II study in malignant glioma (in indications at least in the US was caused
trials for severe pain, with material that is the US). Given the fact that the first Phase I by the fact that the major funding source
extracted from pufferfish livers; adminis- trial with the compound started in March for marine-based drug discovery research
tration of the compound can be intramus- of 2006, it is somewhat surprising that it was the NIH/NCI;[61] it needs to be seen if
cular or subcutaneous.[52] has not been advanced beyond this initial and how this emphasis will change in the
phase of clinical testing.[61] Remarkably, future. I also note that the most recently
3.2 Aplidine the GMP grade material for the clinical discovered marine NP that has either led to
Linear and cyclic (depsi)peptides rep- trials is manufactured using an optimized a drug or even a candidate drug currently
resent an important subgroup of marine bacterial fermentation process that delivers in clinical development is salinosporamide
NPs that can be equipped with a wide a titer of 450 mg/L in shake flasks and of A, a compound that was reported already
range of biological activities.[53] Aplidine 360 mg/L in a large scale fermenter.[60] 14 years ago. A general lack of newer NP
is a cyclic depsipeptide that was originally scaffolds in the development pipeline (i.e.
isolated from the Mediterranean tunicate not limited to marine-derived agents) has
Aplidium albicans[54] and that is related to 4. Conclusions and Outlook also been recognized by others.[62]
the didemnin family of marine NPs that A striking aspect of all successful ma-
are produced by the Caribbean marine tu- In this short review I have highlighted rine-based drug discovery so far (includ-
nicate Trididemnum solidum (Fig. 6).[55] the impact of marine natural products on ing the identification of the vast majority of
Formally, aplidine is a dehydro analog of drug discovery at the levels of marine NP- clinical candidates) is a distinct lack of me-
didemnin B, which was the first marine derived marketed drugs and the current dicinal chemistry impact, in terms of the
NP ever to be advanced to clinical trials in clinical development pipeline. While one targeted optimization of ADME properties.
humans, but whose development as an an- may be tempted to argue that the number of As pointed out earlier, the majority of ma-
ticancer agent was terminated in Phase II. marine-derived drugs is small, this needs rine-derived drugs/candidate drugs that are
Aplidine is a very potent antitumor
agent with a complex mode of action, in-
cluding direct apoptosis-inducing activity,
but also effects on the tumor microenviron- O O
ment.[56] Most recently, it has also been re- O
N
O
N
ported to bind to the translation elongation O O
factor eEF1A2.[57] Aplidine is currently NH O N NH O N
O
undergoing Phase III trials in multiple O
O O O
O
myeloma in combination with dexametha- O
O HO
O
N
N
N O
O HO
O
N
N
N
sone. The drug is produced by chemical NH
H
O
O
NH
H
O
OH
O O O O
synthesis.

3.3 Salinosporamide A
Salinosporamide A (also known as Aplidine Didemnin B
marizomib and NPI-0052) (Fig. 7) is a
halogenated marine NP with an unprec- Fig. 6. Marine cyclodepsipeptides aplidine and didemnin B.
edented structure that was first isolated by
Fenical and co-workers in 2003 from the
Fig. 7. Structure of
marine bacterium Salinispora tropica.[58] Cl salinosporamide A
The genus Salinispora comprises obli- and of the covalent
gate marine actinomycetes that are found in O O
adduct formed with
ocean sediments and the first members of O
O O O the proteasome after
this genus had been described only shortly HN HN NH binding and reaction
O O
before the discovery of salinosporamide A HO HO
with the active site
(also by Fenical).[59] Thus, salinosporamide Thr residue.
A is a very illustrative example for how the
discovery and cultivation of new marine Salinosporamide A
species is intimately related to the discov-
Medicinal cheMistry CHIMIA 2017, 71, No. 10 651

not ADCs are unmodified natural products [1] D. J. Newman, G. M. Cragg, J. Nat. Prod. 2016, McIntosh, J. Varga, J. Rivier, V. de Santos, L. J.
and for those that are not, it was/is mostly 79, 629. Cruz, Science 1985, 230, 1338.
[2] E. Patridge, P. Gareiss, M. S. Kinch, D. Hoyer, [29] For a review, see: G. P. Miljanich, Curr. Med.
synthetic organic chemistry, rather than Drug Discov. Today 2016, 21, 204. Chem. 2004, 11, 3029.
medicinal chemistry, that has driven the [3] D. Camp, A. Garavelas, M. Campitelli, J. Nat. [30] R. W. Teichert, B. M. Olivera, J. M. McIntosh,
discovery and development process as the Prod. 2015, 78, 1370. G. Bulaj, M. P. Horvath, in ‘Venoms to Drugs:
more important enabling chemistry tech- [4] For a recent review, see: D. Benjamin, M. Venom as a Source for the Development of
nology. This said, however, it also needs to Colombi, C. Moroni, M. N. Hall, Nat. Rev. Human Therapeutics’, Ed. G. F. King, London,
Drug Discov. 2011, 10, 868. 2015, 163.
be noted that comprehensive SAR studies [5] For a recent review, see: K. Chiba, A. Kunimoto, [31] K. L. Rinehart, T. G. Holt, N. L. Fregeau, J.
have been conducted on a number of com- Fut. Med. Chem. 2012, 4, 771. G. Stroh, P. A. Keifer, F. Sun, L. H. Li, D. G.
plex marine natural products, including [6] For recent reviews see: a) S. Rizzo, H. Martin, J. Org. Chem. 1990, 55, 4513.
halichondrins,[36] discodermolide,[63] spon- Waldmann, Chem. Rev. 2014, 114, 4621. b) S. [32] A. E. Wright, D. A. Forleo, P. G. Gunawardana,
Wetzel, R. S. Bon, K. Kumar, H. Waldmann, S. P. Gunasekera, F. E. Koehn, O. J. McConnell,
gistatin,[64] bryostatins,[65] migrastatin,[66] Angew. Chem. Int. Ed. 2011, 50, 10800. J. Org. Chem. 1990, 55, 4508.
or apratoxin S4,[67] which have led to the [7] N. Fusetani, in ‘Progress in Molecular and [33] For a recent review on the mechanism(s) of ac-
identification of highly potent analogs Subcellular Biology’, Eds. N. Fusetani, W. tion of trabectedin see: M. D’Incalci, N. Badri,
with significantly simpler structures than Kem, Berlin, Heidelberg, 2009, 1. C. M. Galmarini, P. Allavena, Br. J. Cancer
the parent natural products (with eribulin [8] Y. M. Vaske, P. Crews, in ‘Bioactive Compounds 2014, 111, 646.
from Marine Foods: Plant and Animal Sources’, [34] C. Cuevas, A. Francesch, Nat. Prod. Rep. 2009,
as the prime example). Thus, Wender’s Eds. B. Hernández-Ledesma, M. Herrero, 26, 322.
extensive work on bryostatins has led to Chichester, 2014, 1. [35] E. J. Corey, D. Y. Gin, R. S. Kania, J. Am. Chem.
the discovery of simplified analogs (‘bryo- [9] C. R. Pye, M. J. Bertin, R. S. Lokeya, W. H. Soc. 1996, 118, 9202.
logs’) that may have potential as anti-HIV Gerwick, R. G. Linington, Proc. Natl. Acad. [36] For a review on the discovery of eribulin, see: M.
Sci. 2017, 114, 5601. Yu, W. Zheng, B. M. Seletsky, B. A. Littlefield,
agents or for the treatment of Alzheimer’s [10] R. Montaser, H. Luesch, Future Med. Chem. Y. Kishi, Ann. Rep. Med. Chem. 2011, 46, 227.
disease (reviewed in ref. [65] together with 2011, 3, 1475. [37] Y. Hirata, D. Uemura, Pure Appl. Chem. 1986,
other examples of a ‘Function through [11] Y. Hu, J. Chen, G. Hu, J. Yu, X. Zhu, Y. Lin, S. 58, 701.
Synthesis-Informed Design’ approach). Chen, J. Yuan, Mar. Drugs 2015, 13, 202. [38] R. Bai, K. D. Paull, C. L. Herald, L. Malspeis,
Likewise, targeted medicinal chemistry [12] J. Coll, Chem. Rev. 1992, 92, 613. G. R. Pettit, E. Hamel, J. Biol. Chem. 1991, 266,
[13] F. Flam, Science 1994, 266, 1324. 15882.
work on new eribulin analogs has led to [14] D. Kelman, Y. Kashman, R. T. Hill, E. [39] A. E. Prota, K. Bargsten, J. F. Díaz, M. Marsh,
compounds that are no longer susceptible Rosenberg, Y. Loya, Pure Appl. Chem. 2009, C. Cuevas, M. Liniger, C. Neuhaus, J. M.
to P-glycoprotein mediated drug efflux[68] 81, 1113. Andreu, K.-H. Altmann, M. O. Steinmetz, Proc.
and/or are orally bioavailable (up to 20% [15] U. Hentschel, J. Piel, S. M. Degnan, M. W. Natl. Acad. Sci. USA 2014, 111, 13817.
Taylor, Nat. Rev. Microbiol. 2012, 10, 641. [40] For a review on the chemistry of halichon-
vs. 3% for eribulin).[69] [16] M. W. Taylor, R. Radax, D. Steger, M. Wagner, drins, see: K. L. Jackson, J. A. Henderson, A. J.
Given the pace of new compound dis- Microbiol. Mol. Biol. Rev. 2007, 71, 295. Phillips, Chem. Rev. 2009, 109, 3044.
covery from marine sources and in light [17] U. R. Abdelmohsen, K. Bayer, U. Hentschel, [41] For a review on the discovery and development
of the unfathomable species diversity of Nat. Prod. Rep. 2014, 31, 381. of brentuximab vedotin, see: P. D. Senter, E. L.
the marine environment, it is safe to pre- [18] a) J. W. Blunt, B. R. Copp, R. A. Keyzers, M. Sievers, Nat. Biotechnol. 2012, 30, 631.
H. G. Munro, M. R. Prinsep, Nat. Prod. Rep. [42] G. R. Pettit, J. K. Srirangam, J. Barkoczy, M.
dict that we will witness the discovery of 2017, 34, 235; b) J. W. Blunt, B. R. Copp, R. A. D. Williams, M. R. Boyd, M. E. Hamel, R. K.
many new bioactive scaffolds from marine Keyzers, M. H. Munro, M. R. Prinsep, Nat. Prod. Pettit, F. Hogan, R. Bai, J.-C. Chapuis, S. C.
organisms in the years to come. To suc- Rep. 2016, 33, 382; c) J. W. Blunt, B. R. Copp, McAllister, J. M. Schmidt, Anti-Cancer Drug
cessfully leverage these basic discoveries R. A. Keyzers, M. H. G. Munro, M. R. Prinsep, Des. 1998, 13, 243.
Nat. Prod. Rep. 2015, 32, 116; d) J. W. Blunt, [43] G. R. Pettit, Y. Kamano, C. L. Herald, A. A.
for drug discovery research will require the B. R. Copp, R. A. Keyzers, M. H. G. Munro, M. Tuinman, F. E. Boettner, H. Kizu, J. M. Schmidt,
continued development of appropriate fer- R. Prinsep, Nat. Prod. Rep. 2014, 31, 160; e) J. L. Baczynskyj, K. B. Tomer, R. J. Bontems, J.
mentation methods for marine organisms W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Am. Chem. Soc. 1987, 109, 6883.
(to enable direct development of a marine Munro, M. R. Prinsep, Nat. Prod. Rep. 2013, 30, [44] A. B. Waight, K. Bargsten, S. Doronina, M. O.
NP and/or to provide sufficient quantities 237; f) J. W. Blunt, B. R. Copp, R. A. Keyzers, Steinmetz, D. Sussman, A. E. Prota, PLoS One
M. H. G. Munro, M. R. Prinsep, Nat. Prod. Rep. 2016, 11, e0160890/1.
of material for semisynthesis); at the same 2012, 29, 144; g) J. W. Blunt, B. R. Copp, R. [45] R. Bai, G. R. Pettit, E. Hamel, Biochem.
time, the power of organic synthesis and A. Keyzers, M. H. G. Munro, M. R. Prinsep, Pharmacol. 1990, 39, 1941.
medicinal chemistry will have to come Nat. Prod. Rep. 2011, 28, 196; h) J. W. Blunt, [46] This information is taken from the FDA label
to bear on SAR evaluations and lead op- B. R. Copp, M. H. G. Munro, P. T. Northcote, for Lovaza®.
M. R. Prinsep, Nat. Prod. Rep. 2010, 27, 165; i) [47] http://marinepharmacology.midwestern.edu/
timization. From a personal perspective, J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Accessed on June 25, 2017.
perhaps most important will be the assess- Northcote, M. R. Prinsep, Nat. Prod. Rep. 2009, [48] L. Paz-Ares, M. Forster, V. Boni, S.
ment of marine NPs for as broad a range of 26, 170. Szyldergemajn, J. Corral, S. Turnbull, A.
bioactivities as possible, in order to ensure [19] A number of 22 000 known marine NP has been Cubillo, C. F. Teruel, I. L. Calderero, M.
the full exploitation of their structural di- quoted for 2011 in ref. [20]. In the period be- Siguero, P. Bohan, E. Calvo, Invest. New Drugs
tween 2012 and 2015 ca. 5000 new marine NP 2017, 35, 198.
versity at the biological level. have been reported.[18] [49] C. Beinat, S. D. Banister, M. Herrera, V. Law,
[20] W. H. Gerwick, B. S. Moore, Chem. Biol. 2012, M. Kassiou, CNS Drugs 2015, 29, 529.
Acknowledgements 19, 85. [50] For a review on the distribution and biosynthet-
The help of Simon Glauser and Dr. Bernhard [21] G. E. Martin, eMagRes. 2012, 1, 883. ic origin of TTX, see: R. Chau, J. A. Kalaitzis,
Pfeiffer in editing and proof-reading the manu- [22] T. F. Molinski, D. S. Dalisay, S. L. Lievens, J. P. B. A. Neilan, Aqu. Toxicol. 2011, 104, 61.
script is acknowledged. Saludes, Nature Rev. Drug Discov. 2009, 8, 69. [51] F. R. Nieto, E. J. Cobos, M. Á. Tejada, C.
[23] I. Paterson, E. A. Anderson, Science 2005, 310, Sánchez-Fernández, R. González-Cano, C. M.
451. Cendán, Mar. Drugs 2012, 10, 281.
Received: July 11, 2017 [24] W. Bergmann, R. J. Feeney, J. Org. Chem. 1951, [52] N. A. Hagen, L. Cantin, J. Constant, T. Haller,
16, 981. G. Blaise, M. Ong-Lam, P. du Souich, W. Korz,
[25] W. Bergmann, R. J. Feeney, J. Org. Chem. 1955, B. Lapointe, Pain Res. Manag. 2017, 1.
20, 1501. [53] For a recent review on marine bioactive pep-
[26] J. Bertin, S. L. Schwartz, J. Lee, A. Korobey- tides, see: R. C. F. Cheung, T. B. Ng, J. H.
nikov, P. C. Dorrestein, L. Gerwick, W. H. Wong, Mar. Drugs 2015, 13, 4006.
Gerwick, J. Nat. Prod. 2015, 78, 493. [54] K. L. Rinehart, A. M. Lithgow-Bertelloni, PCT
[27] D. J. Newman, G. M. Cragg, K. M. Snader, Nat. Int. Pat. Appl. WO 91.04985, Apr. 18, 1991; GB
Prod. Rep. 2000, 17, 215. Appl. 89/22,026, Sept. 29, 1989; Chem Abstr.
[28] B. M. Olivera, W. R. Gray, R. Zeikus, J. M. 1991, 115, 248086q.
652 CHIMIA 2017, 71, No. 10 Medicinal cheMistry

[55] For reviews on didemnins, see: a) M. D. Vera, 17, 2175; b) B. C. Potts, K. S. Lam, Mar. Drugs [67] Q.-Y. Chen, Y. Liu, W. Cai, H. Luesch, J. Med.
M. M. Joullie, Med. Res. Rev. 2002, 22, 102; 2010, 8, 835; c) T. A. M. Gulder, B. S. Moore, Chem. 2014, 57, 3011.
b) J. Lee, J. N. Currano, P. J. Carroll, M. M. Angew. Chem. Int. Ed. 2010, 49, 9346. [68] S. Narayan, E. M. Carlson, H. Cheng, H. Du,
Joullie, Nat. Prod. Rep. 2012, 29, 404. [61] The protracted development of the compound Y. Hu, Y. Jiang, B. M. Lewis, P. Saxton, B. M.
[56] C. M. Galmarini, M. D’Incalci, P. Allavena, maybe related to the demise of the company Seletsky, K. Tendyke, H. Zhang, W. Zheng, B.
Mar. Drugs 2014, 12, 719. Nereus, which sponsored the early trials with A. Littlefield, M. J. Towle, M. J. Yu, Bioorg.
[57] A. Losada, M. J. Muñoz-Alonso, C. García, salinosporamide A. See D. J. Newman, G. M. Med. Chem. Lett. 2011, 21, 1630.
P. A. Sánchez-Murcía, J. F. Martínez-Leal, J. Cragg, Planta Med. 2016, 82, 775. [69] S. Narayan, E. M. Carlson, H. Cheng, K.
M. Dominguez, M. P. Lillo, F. Gago, C. M. [62] M. Butler, A. A. B. Robertson, M. A. Cooper, Condon, H. Du, S. Eckley, Y. Hu, Y. Jiang, V.
Galmarini, Sci. Rep. 2016, 6, 35100. Nat. Prod. Rep. 2014, 31, 1612. Kumar, B. M. Lewis, P. Saxton, E. Schuck, B.
[58] R. H. Feling, G. O. Buchanan, T. J. Mincer, C. [63] A. B. Smith, III, B. S. Freeze, Tetrahedron M. Seletsky, K. Tendyke, H. Zhang, W. Zheng,
A. Kauffman, P. R. Jensen, W. Fenical, Angew. 2008, 64, 261. B. A. Littlefield, M. J. Towle, M. J. Yu, Bioorg.
Chem. Int. Ed. 2003, 42, 355. [64] A. B. Smith, III, C. A. Risatti, O. Atasoylu, C. S. Med. Chem. Lett. 2011, 21, 1634.
[59] T. J. Mincer, P. R. Jensen, C. A. Kauffman, W. Bennett, J. Liu, H. Cheng, K. TenDyke, Q. Xu,
Fenical, Appl. Environ. Microbiol. 2002, 68, J. Am. Chem. Soc. 2011, 133, 14042.
5005. [65] P. A. Wender, R. V. Quiroz, M. C. Stevens, Acc.
[60] For reviews on the discovery and development Chem. Res. 2015, 48, 752.
of salinosporamide A, see: a) W. Fenical, P. [66] For a review, see: E. Giralt, D. Lo Re, Molecules
R. Jensen, M. A. Palladino, K. S. Lam, G. K. 2017, 22, 198.
Lloyd, B. C. Potts, Bioorg. Med. Chem. 2009,