Part F | 29.2
714 Part F Marine Derived Metabolites
choline receptors, while -conotoxins inhibit skeletal
muscle voltage-gated Na
C channels [29.16]. Both (˛and -conotoxins) produce paralysis through blocking neuromuscular transmission in vertebrates, which
limits the clinical application of these conotoxins.
The !-conotoxins, are recognized as inhibitors of ion
of VGCCs in an isoform-dependent manner, a property that explains the exerted role of paralysis in the
prey. The synthetic equivalent of !-conotoxin MVIIA
from conus is commercially known as Ziconotide,
or SNX-111 and is considered as the first venomderived drug of VGCC antagonists. It is used as an
analgesic in neuropathic pain with clinical applications [29.17–19]. Analgesia is provided by this toxin
via binding to N-type voltage-sensitive calcium channels in the spinal cord. The fact that ziconotide does
not easily cross the blood–brain barrier because of
its poor tissue penetration as well as its hypotensive effect, promoted the development of the intrathecal adapted methods for its delivery. Thus, a special delivery strategy via an intrathecal catheter or by
an external microinfusion device [29.10, 11, 20] has
led to improved patient treatability and acceptability of this venom toxin as a pharmaceutical. Studies
conducted on post Phase III clinical trials corroborate the benefiting effect of intrathecal ziconotide in
living systems. Strikingly, ziconotide is 1000 times
more potent than morphine and unlike opiates does
not produce tolerance [29.21]. Another !-conotoxin,
CVID from Conus catus, in spite of assessed as
the most potent of all N-type VGCC peptide blockers, finally exhibited the Achilles tendon problematic
of marine toxins: the severe side effects in clinical trials [29.22–24]. Small molecules derived from
!-conotoxins, Z160, have actually advanced through
Phase II clinical trials aimed to increase oral bioavailability [29.20, 24], and are intolerant of or refractory
to other treatments (systemic analgesics, adjunctive
therapies or IT morphine). The European Commission approved ziconotide for the treatment of severe, chronic pain in patients, specifically requiring
intrathecal analgesia [29.11, 25]. Actually, Ziconotide
is commercialized under the trade name of Prialt by
pharmaceutical companies in USA and the European
Union.
29.2.2 Ecteinascidins: A Therapy for Soft
Tissue Sarcoma
Ecteinascidins (ET-743) are marine alkaloid, anticancer
agents isolated from Ecteinascidia turbinate, a colonial tunicate found in the Caribbean and Mediterranean
Sea [29.26]. ET-743 and its N-demethylated analog
ET-729 are lactone members. Their structural features
are a distinctive feature of the ecteinascidins [29.11].
Structurally, they are conformed of three fused tetrahydroisoquinoline rings connected to the base structure by
a thioether bridge, giving rise to a ten-membered lactone, which is characteristic of ecteinascidins [29.26,
27]. These alkaloids are produced by semisynthesis
after controlled fermentation of the marine bacterium
Pseudomonas fluorescens, which leads to ET-743 from
cyanosafracin B [29.28]. ET-743 also is named trabectedin or goes under the trade name Yondelis
(Fig. 29.1).
The covalent binding of trabectedin to the deoxyribonucleic acid (DNA) minor groove has been used
to explain its mechanism of action [29.29]. Trabectedin interacts with binding proteins of the nucleotide
excision repair (NER) system [29.30, 31] to exert its
cytotoxic activity [29.10] and induces an apoptotic effect by arrest at the G2/M stage of the cell cycle of
tumors; a condition that seems independent of p53.
Studies with ET-743 have shown dose limiting toxicities that include neutropenia and thrombocytopenia,
and transaminase elevation [29.32]. Analysis of the effects of trabectedin in vivo and in vitro systems have
evidenced positive results in the control of soft tissue
sarcoma [29.33], and it has been approved in the European Union for the treatment of refractory ovarian
cancer.
29.2.3 Cytarabine to Treat
Meningeal Leukemia;
Vidarabine, An Ophthalmic,
Non-Corticosteroid Antiviral
The synthetic pyrimidine nucleoside Cytarabine was
developed from the nucleoside spongothymidine, originally isolated from the Caribbean sponge Tethya
crypta, the first-derived product of which was
named Ara-C, arabinosylcytosine, or cytosine arabinoside (Fig. 29.1). Cytarabine is a specific cytotoxic compound that inhibits DNA polymerase
and DNA synthesis by competition for deoxycitidine triphosphate, once converted to cytosine arabinoside triphosphate. In treatment programs it is
also named antimetabolites; it main role is slowing or stopping the growth of cancer cells in human body. Vidarabine is the named assigned to
the synthetic purine nucleoside, arabinofuranosyl adenine, or adenine arabinoside (Ara-A) developed from
714 Part F Marine Derived Metabolites
choline receptors, while -conotoxins inhibit skeletal
muscle voltage-gated Na
C channels [29.16]. Both (˛and -conotoxins) produce paralysis through blocking neuromuscular transmission in vertebrates, which
limits the clinical application of these conotoxins.
The !-conotoxins, are recognized as inhibitors of ion
of VGCCs in an isoform-dependent manner, a property that explains the exerted role of paralysis in the
prey. The synthetic equivalent of !-conotoxin MVIIA
from conus is commercially known as Ziconotide,
or SNX-111 and is considered as the first venomderived drug of VGCC antagonists. It is used as an
analgesic in neuropathic pain with clinical applications [29.17–19]. Analgesia is provided by this toxin
via binding to N-type voltage-sensitive calcium channels in the spinal cord. The fact that ziconotide does
not easily cross the blood–brain barrier because of
its poor tissue penetration as well as its hypotensive effect, promoted the development of the intrathecal adapted methods for its delivery. Thus, a special delivery strategy via an intrathecal catheter or by
an external microinfusion device [29.10, 11, 20] has
led to improved patient treatability and acceptability of this venom toxin as a pharmaceutical. Studies
conducted on post Phase III clinical trials corroborate the benefiting effect of intrathecal ziconotide in
living systems. Strikingly, ziconotide is 1000 times
more potent than morphine and unlike opiates does
not produce tolerance [29.21]. Another !-conotoxin,
CVID from Conus catus, in spite of assessed as
the most potent of all N-type VGCC peptide blockers, finally exhibited the Achilles tendon problematic
of marine toxins: the severe side effects in clinical trials [29.22–24]. Small molecules derived from
!-conotoxins, Z160, have actually advanced through
Phase II clinical trials aimed to increase oral bioavailability [29.20, 24], and are intolerant of or refractory
to other treatments (systemic analgesics, adjunctive
therapies or IT morphine). The European Commission approved ziconotide for the treatment of severe, chronic pain in patients, specifically requiring
intrathecal analgesia [29.11, 25]. Actually, Ziconotide
is commercialized under the trade name of Prialt by
pharmaceutical companies in USA and the European
Union.
29.2.2 Ecteinascidins: A Therapy for Soft
Tissue Sarcoma
Ecteinascidins (ET-743) are marine alkaloid, anticancer
agents isolated from Ecteinascidia turbinate, a colonial tunicate found in the Caribbean and Mediterranean
Sea [29.26]. ET-743 and its N-demethylated analog
ET-729 are lactone members. Their structural features
are a distinctive feature of the ecteinascidins [29.11].
Structurally, they are conformed of three fused tetrahydroisoquinoline rings connected to the base structure by
a thioether bridge, giving rise to a ten-membered lactone, which is characteristic of ecteinascidins [29.26,
27]. These alkaloids are produced by semisynthesis
after controlled fermentation of the marine bacterium
Pseudomonas fluorescens, which leads to ET-743 from
cyanosafracin B [29.28]. ET-743 also is named trabectedin or goes under the trade name Yondelis
(Fig. 29.1).
The covalent binding of trabectedin to the deoxyribonucleic acid (DNA) minor groove has been used
to explain its mechanism of action [29.29]. Trabectedin interacts with binding proteins of the nucleotide
excision repair (NER) system [29.30, 31] to exert its
cytotoxic activity [29.10] and induces an apoptotic effect by arrest at the G2/M stage of the cell cycle of
tumors; a condition that seems independent of p53.
Studies with ET-743 have shown dose limiting toxicities that include neutropenia and thrombocytopenia,
and transaminase elevation [29.32]. Analysis of the effects of trabectedin in vivo and in vitro systems have
evidenced positive results in the control of soft tissue
sarcoma [29.33], and it has been approved in the European Union for the treatment of refractory ovarian
cancer.
29.2.3 Cytarabine to Treat
Meningeal Leukemia;
Vidarabine, An Ophthalmic,
Non-Corticosteroid Antiviral
The synthetic pyrimidine nucleoside Cytarabine was
developed from the nucleoside spongothymidine, originally isolated from the Caribbean sponge Tethya
crypta, the first-derived product of which was
named Ara-C, arabinosylcytosine, or cytosine arabinoside (Fig. 29.1). Cytarabine is a specific cytotoxic compound that inhibits DNA polymerase
and DNA synthesis by competition for deoxycitidine triphosphate, once converted to cytosine arabinoside triphosphate. In treatment programs it is
also named antimetabolites; it main role is slowing or stopping the growth of cancer cells in human body. Vidarabine is the named assigned to
the synthetic purine nucleoside, arabinofuranosyl adenine, or adenine arabinoside (Ara-A) developed from