Camptothecin lactone

Mi, Z., Burke, T.G. Differential interactions of camptothecin lactone and carboxylate forms with human blood components. Biochemistry 1994, 33, 10325-10336. 

The pentacyclic plant alkaloid camptothecin has been a popular synthetic target because of its antitumor activity. Retrosynthetic disconnection to tricyclic intermediate A and chiral lactone B followed from multistrategic planning. 

The procedure may have considerable scope, as shown by the synthesis of a heterocyclic lactone which is an important intermediate in the synthesis of eZ,Z-desoxycamptokhecin, which on oxidation gave camptothecin.12... 

Giovanella BC, Harris N, Mendoza J, Cao Z, Liehr J, Stehlin JS. Dependence of anticancer activity of camptothecins on maintaining their lactone function. Ann NY Acad Sci 2000 922 27-35. 

Joguparthi, V, Xiang, T.-X. and Anderson, B.D. (2007) Liposome transport of hydrophobic drugs gel phase lipid bilayer permeability and partitioning of the lactone form of a hydrophobic camptothecin, DB-67. Journal of Pharmaceutical Sciences, 97, 400-420. 

The pentacyclic quinoline alkaloid camptothecin (1) contains in addition to the quinoline system (rings A and B) a pyndone unit (ring D) and a lactone ring (E) Compound 1 also includes one stereogenic center (at C-20), which has the -configuration... 

Ring E is closed by lactonization with 60% sulfuric acid and warming to 115 C. Simultaneously, the methoxy group is activated (by protonation) with respect to nucleophilic attack by the pyridone nitrogen. Ring C is closed via an SN reaction to produce the target molecule, (+)-camptothecin (1). 

In another synthesis of this alkaloid the tricyclic lactone 30 was prepared by a series of reactions in which most of the steps gave satisfactory yields. Hydrolysis with aqueous oxalic acid and condensation with anthraniladehyde generated compound 31 which had already been converted into camptothecine (21). It should be added that the early promise of this alkaloid as a therapeutic agent in cancer therapy has not been confirmed in clinical trials (22). 

Figure 5.17 shows the interconversion of the lactone form of a semisynthetic analogue of camptothecin to its ring-opened carboxylate form. The lactone form predominates in low pH whereas the ring-opened carboxylate form prevails at neutral and alkaline pH, as illustrated in Figure 5.18. 

The lactone form of an analogue of camptothecin converts to its ring-opened carboxylate form. Both forms are in equilibrium. The following degradation data of the lactone form were collected ... 

Topotecan (toe poe TEA can) has recently been approved for the treatment of metastic ovarian cancer. It is a semi-synthetic derivative of an earlier drug, camptothecin. Topotecan has a complicated multiring structure containing a lactone ring that is essential for activity. The drug inhibits topoisomerase I, which is essential in the replication of DNA in human cells (Figure 38.23). Unlike etoposide, which inhibits... 

Camptothecins. The alkaloid camptothecin from Camptotheca acuminata (Nyssaceae) and Mappiafoetida (Icacinaceae) has a pyranoindolizoquinoline structure (Phe pyridine C4N C5N C5L) involving the fusion of quinoline (Phe pyridine), indolizidine (C4N C5N ) and C5 lactone (C5L) rings. Camptothecin is a topoisomerase I inhibitor and is a potent cytotoxic and antitumour compound that is used clinically as an anticancer... 

Our group is currently working on the formulation of another potent anticancer drug, camptothecin, that is clinically inactive due to its very low water solubility and poor stability under physiological pH, which causes the drug to be converted from its active lactone form to its inactive carboxylate form. Two different amphiphilic... 

The camptothecin synthesis of Shen/Dani-shefsky [16] (Scheme 8) starts with the construction of the D ring reaction of 46 with 47 affords 48. The next step (48 49) introduces the C20 ethyl group. Hydroxymethylation of 49 delivers lactone SO. The B ring of the camptothecin precursor 52 should be accomplished by a Friedlander condensation of 10 with 11. For this purpose, a keto group at C2 of the C,D,E ring building block had to be installed. Shen and Danishefsky solved this problem by combination of an aldol condensation (50 —> 51) and a subsequent ozonolysis (51 11). Important for... 

Michael addition of the potassium enolate of cy-anacetamide (14) provided the precursor 55 of the pyridone 56. This intermediate was obtained by oxidation of 55 with t-BuOOH in the presence of 20 mol % SeOj on Si02. The addition of 10 % H2SO4 to the reaction mixture directly delivered the lactone 56. Lactones like 56 are not easy to reduce, but treatment with NaBH4/CeCl3 provided the diol 57 in 95 % yield. 57 could be easily converted to camptothecin by heating it to 115 °C in 60 % H2SO4 in EtOH. 

Camptothecin (CRT, 6, Figure 2.2) was first isolated from the Chinese ornamental tree Camptotheca acuminata Decne, also known as the tree of joy and tree oflove. It occurs in different plant parts such as the roots, twigs, and leaves. It is a member of the quinoline alkaloid group and consists of a pentacyclic ring structure that includes a pyrrole quinoline moiety and one asymmetric center within the a-hydroxy lactone... 

Karenitedn (11, Figure 2.2) is a very lipophilic compound that exhibits more potent cytotoxic activity than camptothecin with both in vitro and in vivo scenarios. In addition to superior in vitro potency, its increased lactone stability and enhanced oral bioavailability are potential clinical advantages [108]. Karenitecin showed significant activity in metastatic melanoma and the dose-limiting toxicity consisted of neutropenia and thrombocytopenia [109]. 

In contrast to the structurally related topotecan, irinotecan is a prodrug, which has to be converted to its active form, SN-38 (4,30). Cleavage of the side-chain, a bulky piperidino moiety, at the CIO position is rapidly catalysed by carboxylesterases after intravenous administration. SN-38 (7-ethyl-lO-hydroxy-camptothecin) is 1000 times more potent than the parent compound. There is an equilibrium between the active lactone and the inactive carboxylated forms in a pH- and protein-dependent manner for both irinotecan and SN-38 (31,32). 

Sawada, S., Yaegashi, T., Furuta, T., Yokokura, T., Miyasaka, T. Chemical modification of an antitumor alkaloid, 20(S)-camptothecin E-lactone ring modified water-soluble derivatives of 7-ethylcamp-tothecin. Chem. Pharm. Bull. 1993, 41, 310-313. 

Many other analogues of camptothecin have been prepared. Studies of compounds modified on the quinoline ring system have shown that substitutions at C-11 and C-12 normally result in a reduction of activity, while substitutions at C-7, C-9, and C-10 can lead to enhanced activity. The E-ring lactone is important for activity and almost all modifications to this ring have led to less active compounds the homocamptothecins, with an expanded ring E, represent an important exception. ... 

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