compound from C. acuminata extracts was carried out by Keith Palmer and Harold
Taylor. CPT, which is an indole alkaloid was effective against both L1210 and p338
leukemic cells (Wall et al. 1996; Raveendran 2015). C. accuminata is used in the
traditional medical practices to treat leukemia, psoriasis, liver diseases, spleen, and
digestive tract (Govindachari and Viswnathan 1972; Efferth et al. 2007). CPT
displayed extraordinary anticancer action in the initial clinical trials. However, it
showed poor water solubility, which restricted its ready usage in cancer
chemotherapy (Kehrer et al. 2001; Li et al. 2006). Thus, medicinal and synthetic
chemists have established several blends of CPT, and several CPT-derivatives were
developed to increase its anticancer potentials with good results. So far, four CPT
analogues are being permitted by the FDA (Food and Drug Administration), USA
to treat various cancer types. These include irinotecan, topotecan, belotecan, and
fam-trastuzumab deruxtecan (Wall et al. 1996; Samuelsson 2004).
The chemical structure of CPT comprises a planar pentacyclic ring configuration, encompassed with a pyrrolo[3,4-b]-quinoline moiety (rings A, B, and C),
conjugated pyridone moiety (ring D) and one chiral center (positioned at C20)
within the a-hydroxy lactone ring having (S) configuration (E-ring) (Fig. 9.1). The
planar arrangement is believed to be the major factor that inhibits topoisomerase
enzymes activity (https://en.wikipedia.org/wiki/Camptothecin). Some of the problems associated with parent CPT is its susceptibility to hydrolysis, which is mainly
because of the lactone ring structure, as well as considerable toxicity. The
a-hydroxy lactone ring having (S) configuration (E-ring) opening under biological
conditions leads to form the carboxylate open form of CPT. Later, sodium salt of
CPT was proposed and reported with higher solubility than the parent CPT.
Unfortunately, clinical investigations showed reduced efficiency against cancers
associated with severe adverse effects, for example, myelotoxicity and hemorrhagic
cystitis (Adams and Burke 2005; Kacprzak 2013). These drawbacks were later
addressed by many researchers, and eventually, semisynthetic and total synthetic
approaches were used to yield many analogues of CPT. Through the structure
activity relationship (SAR), a detailed understanding on CPT structure was made
and developed few soluble and very active antitumor drugs, namely irinotecan,
topotecan, belotecan, and an active metabolite of irinotecan, named as SN-38
(Fig. 9.2). These aspects are described in detail by a number of review articles
(Zunino et al. 2002; Sriram et al. 2005; Kacprzak 2013; Li et al. 2017; Amin et al.
2018), and readers may refer them for better understanding.
Fig. 9.1 Structure of
camptothecin showing a
planar pentacyclic ring
structure
314
M. K. Swamy et al.
Taylor. CPT, which is an indole alkaloid was effective against both L1210 and p338
leukemic cells (Wall et al. 1996; Raveendran 2015). C. accuminata is used in the
traditional medical practices to treat leukemia, psoriasis, liver diseases, spleen, and
digestive tract (Govindachari and Viswnathan 1972; Efferth et al. 2007). CPT
displayed extraordinary anticancer action in the initial clinical trials. However, it
showed poor water solubility, which restricted its ready usage in cancer
chemotherapy (Kehrer et al. 2001; Li et al. 2006). Thus, medicinal and synthetic
chemists have established several blends of CPT, and several CPT-derivatives were
developed to increase its anticancer potentials with good results. So far, four CPT
analogues are being permitted by the FDA (Food and Drug Administration), USA
to treat various cancer types. These include irinotecan, topotecan, belotecan, and
fam-trastuzumab deruxtecan (Wall et al. 1996; Samuelsson 2004).
The chemical structure of CPT comprises a planar pentacyclic ring configuration, encompassed with a pyrrolo[3,4-b]-quinoline moiety (rings A, B, and C),
conjugated pyridone moiety (ring D) and one chiral center (positioned at C20)
within the a-hydroxy lactone ring having (S) configuration (E-ring) (Fig. 9.1). The
planar arrangement is believed to be the major factor that inhibits topoisomerase
enzymes activity (https://en.wikipedia.org/wiki/Camptothecin). Some of the problems associated with parent CPT is its susceptibility to hydrolysis, which is mainly
because of the lactone ring structure, as well as considerable toxicity. The
a-hydroxy lactone ring having (S) configuration (E-ring) opening under biological
conditions leads to form the carboxylate open form of CPT. Later, sodium salt of
CPT was proposed and reported with higher solubility than the parent CPT.
Unfortunately, clinical investigations showed reduced efficiency against cancers
associated with severe adverse effects, for example, myelotoxicity and hemorrhagic
cystitis (Adams and Burke 2005; Kacprzak 2013). These drawbacks were later
addressed by many researchers, and eventually, semisynthetic and total synthetic
approaches were used to yield many analogues of CPT. Through the structure
activity relationship (SAR), a detailed understanding on CPT structure was made
and developed few soluble and very active antitumor drugs, namely irinotecan,
topotecan, belotecan, and an active metabolite of irinotecan, named as SN-38
(Fig. 9.2). These aspects are described in detail by a number of review articles
(Zunino et al. 2002; Sriram et al. 2005; Kacprzak 2013; Li et al. 2017; Amin et al.
2018), and readers may refer them for better understanding.
Fig. 9.1 Structure of
camptothecin showing a
planar pentacyclic ring
structure
314
M. K. Swamy et al.