Abstract
A series of 4,8-dimethyl-4-phenylsulfonylmethyl-2,3- dioxabicyclo[3.3.l]nonanes, carrying a variety of substituents at position-8 (4) were prepared by a short and efficient method from R-(+)-limonene. Key reactions include thiol oxygen cooxidation, and alkylation and acylation of a sterically hindered tertiary alcohol compatible with the endoperoxy functionality. Some of compounds 4, which are structurally related to yingzhaosu A (2), were found to exhibit in vitro antimalarial activity comparable to that of artemisinin (1) and superior to that of arteflene (3).
| Original language | English |
|---|---|
| Pages (from-to) | 903-908 |
| Number of pages | 6 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 8 |
| Issue number | 8 |
| DOIs | |
| State | Published - 21 Apr 1998 |
| Externally published | Yes |
Bibliographical note
Funding Information:The data for antimalarial activity in vitro summarized in Table 1 indicates that, except for the case of derivatives 13a and 13b, blocking the free hydroxy group in 7 is associated with increase in antimalarial activity. Furthermore, it was found that compounds of the "a" series are usually slightly more reactive than their corresponding C-4 epimers of the "b" series. 29 In conclusion, thiol oxygen cooxidation of R-(+)-limonene (5), followed by alkylation or acylations of a sterically hindered tertiary alcohol under conditions compatible with the peroxide function of the 2,3-dioxabicyclo\[3.3.1\]nonanes ystem, provided a series of readily available and potent antimalarial agents. 4-Phenylsulfonylmethyl-2,3-dioxabicyclo\[3.3.1\]nonanes8 a, 10a, 10b, and 14a exhibit in vitro antimalarial activity comparable to that of arteflene (2), 12,13 of the drug artemisinin (1) and of 1,2,4-trioxanes structurally related to (1). 4-9,19-21,30-33 Acknowledgment: This research was supported by grant No. 94-102 from the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel. The U.S. NIH and the Burroughs Wellcome Fund supported the antimalarial in vitro studies at Johns Hopkins.
Funding
The data for antimalarial activity in vitro summarized in Table 1 indicates that, except for the case of derivatives 13a and 13b, blocking the free hydroxy group in 7 is associated with increase in antimalarial activity. Furthermore, it was found that compounds of the "a" series are usually slightly more reactive than their corresponding C-4 epimers of the "b" series. 29 In conclusion, thiol oxygen cooxidation of R-(+)-limonene (5), followed by alkylation or acylations of a sterically hindered tertiary alcohol under conditions compatible with the peroxide function of the 2,3-dioxabicyclo\[3.3.1\]nonanes ystem, provided a series of readily available and potent antimalarial agents. 4-Phenylsulfonylmethyl-2,3-dioxabicyclo\[3.3.1\]nonanes8 a, 10a, 10b, and 14a exhibit in vitro antimalarial activity comparable to that of arteflene (2), 12,13 of the drug artemisinin (1) and of 1,2,4-trioxanes structurally related to (1). 4-9,19-21,30-33 Acknowledgment: This research was supported by grant No. 94-102 from the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel. The U.S. NIH and the Burroughs Wellcome Fund supported the antimalarial in vitro studies at Johns Hopkins.
| Funders | Funder number |
|---|---|
| National Institutes of Health | |
| Burroughs Wellcome Fund | |
| Bloom's Syndrome Foundation | |
| Johns Hopkins University | |
| United States-Israel Binational Science Foundation |