Monorden (radicicol), a resorcylic 14-membered lactone, is a macrocyclic natural antibiotic initially isolated from the fungus Monosporium bonorden. Monorden was found to manifest antifungal and antitumor properties. It was shown to be an inhibitor of the v-Src and Ras-Raf-MAPK signaling pathways. Its ability to bind to heat shock protein Hsp90 made it the prototype of a second class of Hsp90 inhibitors, distinct from the chemically unrelated benzoquinone ansamycins. Radicicol inhibited Hsp90 activity by binding to the ATP-binding pocket, subsequently suppressing cell transformation induced by src, ras and mos. Radicicol binds more strongly to Hsp90 than to Grp94, the Hsp90 homolog that resides in the endoplasmic reticulum. In contrast to Hsp90, binding of radicicol to Grp94 requires both the N-terminal ATP/ADP-binding domain as well as the adjacent negatively charged region. Radicicol also specifically binds to yeast Hsp90, Escherichia coli HtpG, with greater homology to bacterial HtpG than to Hsp90 and to and a newly described tumor necrosis factor receptor-interacting protein, Trap-1. Radicicol displayed anti-cancer activity in vitro. It represses estrogen receptor transcriptional activity and inhibits angiogenesis. Radicicol disrupts the ER-Hsp90 heterodimeric complex, thereby generating ER-alpha that is susceptible to ubiquitin/proteasome-induced degradation. Because radicicol is rapidly metabolizes to inactive metabolites in vivo due to its electrophilic nature, no in vivo activity has been observed with this natural product including anti-tumor activity, thus the compound was not considered a viable candidate for clinical evaluation.

Thiolutin is a naturally occurring bicyclic dithiole that was first isolated from Streptomyces luteorectiuli based on its antibiotic activities. Thiolutin inhibits the growth of Saccharomyces cerevisiae and several gram-positive and -negative bacteria by inhibiting DNA-dependent RNA polymerases. It also inhibits the adhesion of endothelial cells, including adhesion of human umbilical vein endothelial cells (HUVECs) to vitronectin, and restricts tumor cell-induced angiogenesis.

Didox is a simple, synthetic antioxidant and a ribonucleotide reductase inhibitor with activity against retroviruses. Didox inhibits retrovirus replication by depleting the deoxynucleotides obligatory for the synthesis of the proviral DNA intermediate of retrovirus replication. It also increases the radiosensitivity of cancer cells by inhibition of ribonucleotide reductase, resulting in a reduction of BCL-2 mediated resistance to apoptosis. Didox has been found to reduce the levels of oxidative injury markers in the brains of HIV patients with dementia. Didox has been evaluated in various phase I and phase II trials but Didox did not demonstrate any efficacy response in patients.