Incorporating azomethine ylide (1,3 dipole) cycloaddition approach

Incorporating diversity in the synthesis of combinatorial
libraries of small molecules for biological screening is an emerging field.1 Rather than being directed toward a single
biological target, diversified libraries can be used to identify new ligands
for a variety of targets. It is hoped that the range of molecular architectures
and potential bonding interactions present in a diversified library can provide
interesting and specific biological activity across a range of targets. Although
various chemical libraries are now available commercially, these remain focused
primarily on so called ‘drug-like’ compounds.2
Because these libraries are concentrated in a relatively narrow region of
chemical structure space, it seems unlikely that they will provide useful
probes for all biological targets of interest.3
The crucial factor for achieving success in drug discovery
is not the size of the library but its structural diversity.4
Several different strategies for library design have therefore
been developed to target the biologically relevant regions of chemical
structure space. DOS has provided powerful probes to investigate biological
mechanisms and also served as a new driving force for advancing synthetic
organic chemistry.

To provide cyclic and
heterocyclic compounds with a high degree of structural complexity as well as skeletal and stereochemical diversity, dipolar
cycloaddition reaction has emerged as a potential tool.13 Its ability to generate new stereocenters has allowed it to contribute very much to the
development of stereo structure-activity relationships during screening
campaigns. In particular, the sequential
azomethine ylide (1,3 dipole) cycloaddition approach has
emerged as one of the efficient strategies which can provide diverse spirooxindoles
in an operationally simple procedure from readily available chemical reagents.14 Keeping the above facts
in mind we started our journey of preparing diversely functionalized heterocycles
via azomethine ylide cycloaddition using simple commercially available5 or synthetic dipolarophiles.6 We then extended it to a new dimension by employing dipolarophiles available from nature like andrographolide7, withaferin A8,
curcumin9 etc. Several compounds have been prepared and biological
activity evaluation revealed some very promising
increment in activity.10-12 In continuation of
our molecular diversity programme, very recently we have synthesized various super curcumin analogues9 to overcome the
drawbacks related to the bioavailability of curcumin (less water solubility, easy metabolism and excretion) with comparable
or better efficacy. An equally compelling motivation for their synthesis lies
in their unique and formidable structure, the
central feature being the biologically important
curcumin and isatin (oxindole) units.9 We have so far
succeeded in synthesizing a library of pyrrolizidino spirooxindolo curcumins, some with better and equal cytotoxic/antioxidant and
antibacterial activity15 but with
much more specificity and solubility compared to curcumin. These results of biological
evaluation encouraged us to construct a better diversified library applying the sequential azomethine
ylide cycloaddition strategy, coupling
isatin, substituted isatins or acenapthoquinone with proline or thioproline as
the amino acid component.