10-Hydroxy-camptothecin

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Rivory LP, Bowles MR, Robert J et al. Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), by human liver carboxylesterase. Biochem Pharmacol 1996 52 1103-1111. 

The major class of topoisomerase I inhibitors comprise of the camptothecins, while topoisomerase II inhibitors fall into several classes - anthracyclines (e.g. doxorubicin), anthracenediones (mitoxantrone), anthrapyrazoles (bianthrazole), actinomycins (actinomycin D), acridines (m-AMSA), ellipticines (9-hydroxy-ellipticine) and epidophyllotoxins (Etoposide (VP-16) and VM-26). The chemical... 

I hralasi iniermoJecular proton transfer from IO-hydroxy-camptothecin... 

Some ring-substituted (hydroxy or methoxy) camptothecin derivatives were either isolated in nature or obtained synthetically [253,264-267]. The 9-methoxy- and 10-methoxycamptothecin are less active, but 10-hydroxy-camptothecin is more active than the parent alkaloid against leukaemia P388 [253, 264], Both camptothecin and its 10-hydroxy derivative are being used in mainland China for the treatment of liver carcinoma and tumours of the head... 

Examples of GDEPT include irinotecan (CPT-11), a prodrug of 7-ethyl- 10-hydroxy-camptothecin activated by carboxylesterase 5-fluorocytosine, a prodrug of 5-FU activated by cytosine deaminase and cyclophosphamide, a prodrug of 4-hydroxycyclophosphamide activated by cytochrome P450, which degrades into acrolein and phospho-ramide mustard.112-115... 

HCPT (0.364 g 0.01 mmol) and 40% aqueous dimethylamine (12 ml) was added in dichloromethane (50 ml) in which anhydrous potassium carbonate (2.17 g, 15 mmol) has been suspended. The reaction mixture was stirred at room temperature for 5 h, then filtered and solid extracted with ethylacetate (20 ml). The solvent is evaporated in vacuo giving a residue. The residue was triturated with 0.5% aq HCI (50 ml) to dissolve the water-soluble adduct. Water-soluble were partitioned with petroleum ether (3 times 50 ml) and followed by ethylacetate (3 times 50 ml). The aqueous layer was lyophilized as an off white hydrochloride salt of 9-[(dimethylamino)methyl]10-hydroxy(20S)-camptothecin (topotecan hydrochloride) yield 0.236 g (65%). 

The DE ring of camptothecin has been prepared enantioselectively in six steps from 2-fluoropyridine using a halogen dance reaction <95TL(36)7995>. The first total synthesis of dimethyl sulfomycinamate (47) was reported starting from 3-hydroxy-6-methylpyridine (48) <95TL(36)5319>. 

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... 

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). 

The silatecan (DB-67) (21) represents a new generation of camptothecin derivatives (see Table 12) that exhibits a potent in vitro DNA topoisomerase I (TOPl)-mediated DNA-damaging activity, improved blood stability, and holds significant promise for the treatment of human cancers [79]. This new agent was found to be 25-times more lipophilic than camptothecin it incorporates readily into cellular and liposomal bilayers. In addition, its 10-hydroxy functionality enhances drug stability in the presence of human serum albumin. Thus, the net... 

Scheme 8.24. Dihydroxylation reactions used for the synthesis of a-hydroxy carbonyl compounds, (a) A chiral auxiliary approach [102], (b) Application of the Sharpless AD procedure to an intermediate for the synthesis of camptothecin [104].

Cyanosilylation of ketones (4,542-543 5,720). In a total synthesis of natural camptothecin (9), Corey et al used this f-butyldimethylsilyl derivative rather than trimethylsilyl cyanide (5, 720-722) to effect cyanosilylation of a ketone (1). Hydrolysis of the resulting cyano silyl ether to the required amide was not accompanied by desilylation with reversal of cyanohydrin formation. By use of carefully controlled conditions and with dicyclohexyl-18-crown-6-potassium cyanide as catalyst, they were able to convert (1) into the a-hydroxy... 

Takayanta. H., Watanabe, A., Ho.sokawa. M Chiba, K Satoh. T., and Ainii, N. (1998). Synthesis of a new class of camptothecin derivatives, the long-chain fatly acid esters of lO-hydroxy-camptocheciii, as a potent prodrug candidate, and their in vitro metabolic conversion by carboxylesterases. Bioorg. Med. Otem. Let/. 8,415-418. 

Duan K, Zhang X et al (2010) Fabrication of cationic nanomicelle from chitosan-graft-polycaprolactone as the carrier of 7-ethyl-lO-hydroxy-camptothecin. Colloids Surf B 76 475 82... 

A novel and efficient s)mthesis of racemic camptothecin 207 starting from a readily accessible hydroxy pyridine 206 was described. Key steps include a Claisen rearrangement of a functionalized allylic ether, a hindered Heck coupling, and a Eriedlander condensation (Scheme 45) (05OL2989). 

The topo I inhibitor camptothecin (16) is a natural alkaloid isolated from the Chinese tree Camptotheca acuminata it is used to treat gastric, rectal, colon, and bladder cancers. Several natural and synthetic derivatives including 9-amino 17) and 10-hydroxy (IS) camptote-cin, topotecan and irinotecan (20, CPT-ll) / potent antitumor and DNA... 

A total synthesis of 10-hydroxy- and 10-methoxy-camptothecins has been described, but adequate details of the work are difficult to obtain the overall route used appears to be similar to that adopted by the same group in an earlier synthesis of camptothecin. 

R.B. Kolhatkar, P. Swaan, H. Ghandehari, Potential oral delivery of 7-ethyl-lO-hydroxy-camptothecin (SN-38) using poly (amido-amine) dendrimers, Pharm. Res. 25 (7) (2008) 1723-1729. 

Camptothecin is a quinoline alkaloid isolated from the steins of C. acuminata (Cornaceae) [1], and 10-hydroxy camptothecin and 10-methoxy camptothecin were also obtained as minor alkaloids [2]. C. acuminata is an ornamental plant in China. Campthothecin has also been isolated from both the Apocy-naceae and Rubiaceae plant families. 

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