Recent Advances in the Chemistry and Pharmacology of Cryptolepine
189
Cryptolepine (1) was found to be toxic when injected by intraperitoneal (i.p.) injection following two daily doses of 20 mg/kg [40]. It is likely that toxicity is related to
DNA-intercalation, inhibition of DNA synthesis, and inhibition of topoisomerase II
[41]. X-ray crystallography of cryptolepine crystallized with specific DNA oligomers
showed that 1 selectively intercalates between non-alternating C-G base pairs [42].
The failure of oral cryptolepine (1) to cure malaria in mice is probably due to
metabolism and/or pharmacokinetic factors as discussed in Section 10.1.
Recently, compound 1 has been shown to have potent activity against P. falciparum
(N54) late stage (IV/V) gametocytes (IC 50 = 1.97 μM) [43], which could be significant for the elimination of malaria as antimalarials with activity against the sexual
stages as well as the asexual stages (liver and asexual red blood cell stages) that will
be required [44]. In vitro combination studies against asexual blood stages of P. falciparum indicated that 1 exhibits synergism with amodiaquine, additive effects with
chloroquine and lumefantrine but antagonism with mefloquine [43]. In vitro synergies between 1 and artemisinins (artesunate, artemether, and dihydroartemisinin) as
well as in vivo synergy between 1 and artesunate in P. berghei (NK-65) infected
mice have been reported with no significant toxicity observed [45]. In another study,
1 was shown to act synergistically with the diterpene xylopic acid when administered
orally to mice infected with P. berghei [46]. No significant toxicity to the kidney,
liver, and spleen was observed but the testes were affected adversely at higher doses.
8.3.2 Development of Antimalarial Agents
The antiplasmodial mode of action of 1 has been shown to be due, at least in part, to
the inhibition of hemozoin formation, raising the possibility that it may be possible
to prepare cryptolepine analogs that retain potent activity against Plasmodium spp.
but without the DNA-intercalating ability that could be responsible for toxicity [40].
A number of halogenated analogs of 1 were prepared by employing methodology
based on that of Holt and Petrow from 1947 [9] (Fig. 4), using substituted derivatives of 9 and/or 17 as starting materials [10, 40]. Several di-halogenated cryptolepine
analogs were found to be up to 10-fold more potent than the parent compound against
P. falciparum in vitro, and also suppressed parasitemia in P. berghei-infected mice
by 90% when given by intraperitoneal injection at 25 mg/kg/day without apparent
toxicity to the mice [10]. The best studied compound is 2,7-dibromocryptolepine
(43) (Fig. 11) which, in common with 1, inhibits the formation of hemozoin but, in
contrast, does not appear to intercalate into DNA, as shown by thermodenaturation
studies (T m values 4 and 9°C for 43 and 1, respectively, with values below 5°C
considered to be due to non-specific binding to DNA) [10]. Experiments have indicated that the increased potency of 43 is neither due to more potent inhibition of
hemozoin formation nor due to increased accumulation of this basic compound into
the acidic parasite food vacuole compared to 1, suggesting that a second, currently
unknown mechanism of action may be operating [10]. When treating malaria, two
drugs with differing modes of action are usually given together in order to reduce
the risk of malaria parasite resistance developing. Dual-acting compounds such as
189
Cryptolepine (1) was found to be toxic when injected by intraperitoneal (i.p.) injection following two daily doses of 20 mg/kg [40]. It is likely that toxicity is related to
DNA-intercalation, inhibition of DNA synthesis, and inhibition of topoisomerase II
[41]. X-ray crystallography of cryptolepine crystallized with specific DNA oligomers
showed that 1 selectively intercalates between non-alternating C-G base pairs [42].
The failure of oral cryptolepine (1) to cure malaria in mice is probably due to
metabolism and/or pharmacokinetic factors as discussed in Section 10.1.
Recently, compound 1 has been shown to have potent activity against P. falciparum
(N54) late stage (IV/V) gametocytes (IC 50 = 1.97 μM) [43], which could be significant for the elimination of malaria as antimalarials with activity against the sexual
stages as well as the asexual stages (liver and asexual red blood cell stages) that will
be required [44]. In vitro combination studies against asexual blood stages of P. falciparum indicated that 1 exhibits synergism with amodiaquine, additive effects with
chloroquine and lumefantrine but antagonism with mefloquine [43]. In vitro synergies between 1 and artemisinins (artesunate, artemether, and dihydroartemisinin) as
well as in vivo synergy between 1 and artesunate in P. berghei (NK-65) infected
mice have been reported with no significant toxicity observed [45]. In another study,
1 was shown to act synergistically with the diterpene xylopic acid when administered
orally to mice infected with P. berghei [46]. No significant toxicity to the kidney,
liver, and spleen was observed but the testes were affected adversely at higher doses.
8.3.2 Development of Antimalarial Agents
The antiplasmodial mode of action of 1 has been shown to be due, at least in part, to
the inhibition of hemozoin formation, raising the possibility that it may be possible
to prepare cryptolepine analogs that retain potent activity against Plasmodium spp.
but without the DNA-intercalating ability that could be responsible for toxicity [40].
A number of halogenated analogs of 1 were prepared by employing methodology
based on that of Holt and Petrow from 1947 [9] (Fig. 4), using substituted derivatives of 9 and/or 17 as starting materials [10, 40]. Several di-halogenated cryptolepine
analogs were found to be up to 10-fold more potent than the parent compound against
P. falciparum in vitro, and also suppressed parasitemia in P. berghei-infected mice
by 90% when given by intraperitoneal injection at 25 mg/kg/day without apparent
toxicity to the mice [10]. The best studied compound is 2,7-dibromocryptolepine
(43) (Fig. 11) which, in common with 1, inhibits the formation of hemozoin but, in
contrast, does not appear to intercalate into DNA, as shown by thermodenaturation
studies (T m values 4 and 9°C for 43 and 1, respectively, with values below 5°C
considered to be due to non-specific binding to DNA) [10]. Experiments have indicated that the increased potency of 43 is neither due to more potent inhibition of
hemozoin formation nor due to increased accumulation of this basic compound into
the acidic parasite food vacuole compared to 1, suggesting that a second, currently
unknown mechanism of action may be operating [10]. When treating malaria, two
drugs with differing modes of action are usually given together in order to reduce
the risk of malaria parasite resistance developing. Dual-acting compounds such as