Design and Synthesis of Natural Product Hybrids as New
Chemical Entities in Drug Discovery and Development
One of
the terminal objectives of organic synthesis from its very
inception has been the search for new compounds that exhibit novel
physical, chemical and biological properties. Such new compounds
have undoubtedly saved countless human lives, alleviated pain and
suffering, extended human longevity, and has positively impacted
the global economy. In spite of the miraculous breakthroughs
however, society continues to be faced with numerous challenges
arising in part from drug resistance, the emergence of new forms of
cancers, and the surfacing of new strains of microbial
pathogens.
In this quest
for biologically active new chemical entities, both human intuition
and leads from Nature have played pivotal roles. Nature makes
natural products of mystifying diversity and complexity and these
are generally derived through specific biosynthetic pathways
leading to a particular class of compounds with specialized
functions. Accordingly, humanity has learned to harness natural
sources for the vast majority of bioactive compounds in medical use
today. Approximately 40% of the drugs that have been approved are
either natural products or derivatives and analogues thereof. Among
anticancer and anti-infective agents, the percentage is even
estimated to exceed 70%, including such well-known examples as
penicillin G and paclitaxel (taxol). Indeed, organ transplantation,
one of the major miracles of modern medicine, would not have been
possible without immunosuppressive natural products such as
cyclosporin A and rapamycin.
Our
current research efforts are geared toward a further harnessing of
nature’s structural variety by combining two or more natural
products to form hybrids. The anticipated outcome is to generate
new chemical entities with enhanced characteristics, particularly
the therapeutic spectrum, based on natural product leads. Synthesis
of such entities typically involves intricate synthetic
manipulations for structural integration or simple straightforward
manipulation of functional groups.
Thus, a
series of hybridized systems with a steroidal substructure are
being generated. The selection of a steroidal nucleus as the base
for these systems stems from the established precedence that the
estrogen receptor is present in higher concentrations in
carcinogenic tissues (breast, ovarian, prostatic and endometrial)
than in normal tissues. Accordingly, estrogens have been
investigated as vectors for cytotoxic agents in the hope that an
increased organ and/or tissue specificity can be achieved through a
selective accumulation of the cytotoxic compound in tumor cells.
Novel systems include hybrids of estrone and combretastatin A4,
estrone and various substituted b-lactams, estrone and phenstatin
systems, and estrone with resveratrol.
The Development of New Antibiotic Antineoplastic
Agents
The development
of new DNA binding agents / Topoisomerase inhibitors as potential
anticancer compounds continues to be an active area of research,
with current investigations aimed at the optimization of
pharmacological properties. This research is geared towards the
design and synthesis of a new series of antibiotic antineoplastics,
employing convergent synthetic methodology. We have integrated the
chemistry and antibiotic properties of two classes of antibiotics -
the ‘DNA-intercalating’ anthracyclines and the ionophoretic
polyether antibiotics. The resulting hybridized structures will
retain the topoisomerase II inhibitory characteristics of the
anthracyclines, coupled with the ion-transporting properties of the
spiroketal-containing polyether antibiotics. The paradigm of
cytotoxic anticancer agents is doxorubicin, a Type I anthracycline,
which has been in use since the late 1960’s. Doxorubicin is still
among the most widely prescribed and effective of antineoplastic
agents. Doxorubicin has been called the most active single agent
against cancer because of its broad anti-tumor spectrum, but there
still remain some important tumor types (e.g. colon, lung) that do
not respond; an even broader spectrum is needed. Clinicians have
learned how to manage the toxic side effects – acute
myelosuppression and chronic cardio-toxicity that were recognized
early in the clinical application of doxorubicin. Its use however,
still imposes treatment limitations (on dose level and on the
number of drug courses). Less toxic analogues would clearly provide
significant therapeutic benefits.