3.2 Designing for Mainly Dual Activity
69
The second general design steps then usually focus on the core framework but
keeping in mind the potential for new attached groups to be included. For example,
topology and electrostatics can be modified by having the heteroatom in different
ring sites and also introducing different atoms in the ring architecture. In embarking
on this particular approach it is worthwhile initially assessing the maximum number
of isomeric heterocyclic skeletons that may be possible to give some idea of the
scope of the new chemical structural space which might be attainable. Also such
systematic analysis can suggest possibilitities not previously considered and also
enable directed literature searches to compare what is known with what is not. Aspects
of this approach have been used previously for example in the non-fused and benzfused oxaza and dioxaza-medium sized ring context (Bremner et al. 1982).
For berberine, the theoretical maximum number of ring isomers with one nitrogen
in the 5, 6, 6, 6, 6 fusion of rings in the bent shape is 21 which includes replacement
of oxygen in the fused 5-membered ring and of carbon at sp
3 positions, aromatic
CH positions and quaternary carbon positions, some of which could also result in
incorporation of a positively charged quaternary nitrogen centre. Including another
nitrogen or a different type of ring heteroatom in this system would clearly enable a
significant increase in the number of ring isomer possibilities. In terms of synthetic
approaches to isomeric systems in general, it is also of value to then consider the
general classification of approaches to heterocycles first elaborated by Stoodley and
reported in 1977 (Stoodley 1977). Although published some years ago it is still very
relevant as a starting point for synthetic planning in the organic and medicinal chemistry fields. Three general approaches, which also apply to carbocyclic synthesis,
were formulated by Stoodley and include:
a. Ring construction where the number of rings are increased.
b. Ring interconversion, where the number of rings remain unchanged but the
process may involve:
(i) ring enlargements
(ii) ring contractions, and
(iii) ring relocations where neither ring enlargement nor ring contraction is
involved but where a ring and a group of atoms react to give a new ring
of the same size with a different arrangement of ring atoms. Heteroatom
replacement of a carbon atom in the ring, or another ring atom, could be
involved with no change in ring size or position, as for example in the
conversion of phthalic anhydrides to phthalimides where O is replaced
by N in the fused 5-membered ring.
c. Ring destruction where the number of rings are decreased.
The ring interconversion approach (b iii) involving ring relocation is of particular interest in the medicinal chemistry SAR context especially if it involves only a
one point change. For example, relating this specifically to berberine, could an extra
nitrogen be introduced adjacent to the extant nitrogen replacing carbon 8 or carbon
13a? No shape or little shape change would be expected but significant localised electrostatic potential change is likely. New hetroatom sites can also serve as different
69
The second general design steps then usually focus on the core framework but
keeping in mind the potential for new attached groups to be included. For example,
topology and electrostatics can be modified by having the heteroatom in different
ring sites and also introducing different atoms in the ring architecture. In embarking
on this particular approach it is worthwhile initially assessing the maximum number
of isomeric heterocyclic skeletons that may be possible to give some idea of the
scope of the new chemical structural space which might be attainable. Also such
systematic analysis can suggest possibilitities not previously considered and also
enable directed literature searches to compare what is known with what is not. Aspects
of this approach have been used previously for example in the non-fused and benzfused oxaza and dioxaza-medium sized ring context (Bremner et al. 1982).
For berberine, the theoretical maximum number of ring isomers with one nitrogen
in the 5, 6, 6, 6, 6 fusion of rings in the bent shape is 21 which includes replacement
of oxygen in the fused 5-membered ring and of carbon at sp
3 positions, aromatic
CH positions and quaternary carbon positions, some of which could also result in
incorporation of a positively charged quaternary nitrogen centre. Including another
nitrogen or a different type of ring heteroatom in this system would clearly enable a
significant increase in the number of ring isomer possibilities. In terms of synthetic
approaches to isomeric systems in general, it is also of value to then consider the
general classification of approaches to heterocycles first elaborated by Stoodley and
reported in 1977 (Stoodley 1977). Although published some years ago it is still very
relevant as a starting point for synthetic planning in the organic and medicinal chemistry fields. Three general approaches, which also apply to carbocyclic synthesis,
were formulated by Stoodley and include:
a. Ring construction where the number of rings are increased.
b. Ring interconversion, where the number of rings remain unchanged but the
process may involve:
(i) ring enlargements
(ii) ring contractions, and
(iii) ring relocations where neither ring enlargement nor ring contraction is
involved but where a ring and a group of atoms react to give a new ring
of the same size with a different arrangement of ring atoms. Heteroatom
replacement of a carbon atom in the ring, or another ring atom, could be
involved with no change in ring size or position, as for example in the
conversion of phthalic anhydrides to phthalimides where O is replaced
by N in the fused 5-membered ring.
c. Ring destruction where the number of rings are decreased.
The ring interconversion approach (b iii) involving ring relocation is of particular interest in the medicinal chemistry SAR context especially if it involves only a
one point change. For example, relating this specifically to berberine, could an extra
nitrogen be introduced adjacent to the extant nitrogen replacing carbon 8 or carbon
13a? No shape or little shape change would be expected but significant localised electrostatic potential change is likely. New hetroatom sites can also serve as different