Synthetic Calanolides with Bactericidal Activity against Replicating and Nonreplicating Mycobacterium tuberculosis

It is urgent to introduce new drugs for tuberculosis to shorten the prolonged course of treatment and control drug-resistant Mycobacterium tuberculosis (Mtb). One strategy toward this goal is to develop antibiotics that eradicate both replicating (R) and nonreplicating (NR) Mtb. Naturally occurring (+)-calanolide A was active against R-Mtb. The present report details the design, synthesis, antimycobacterial activities, and structure–activity relationships of synthetic calanolides. We identified potent dual-active nitro-containing calanolides with minimal in vitro toxicity that were cidal to axenic Mtb and Mtb in human macrophages, while sparing Gram-positive and -negative bacteria and yeast. Two of the nitrobenzofuran-containing lead compounds were found to be genotoxic to mammalian cells. Although genotoxicity precluded clinical progression, the profound, selective mycobactericidal activity of these calanolides will be useful in identifying pathways for killing both R- and NR-Mtb, as well as in further structure-based design of more effective and drug-like antimycobacterial agents

Salutaxel, a Conjugate of Docetaxel and a Muramyl Dipeptide (MDP) Analogue, Acts as Multifunctional Prodrug That Inhibits Tumor Growth and Metastasis

Salutaxel (<b>3</b>) is a conjugate of docetaxel (<b>7</b>) and a muramyl dipeptide (MDP) analogue. Docetaxel (<b>7</b>) has been recognized as a highly active chemotherapeutic agent against various cancers. MDP and its analogues are powerful potentiators of the antitumor actions of various tumor-necrotizing agents. This article documents the discovery of compound <b>3</b> and presents pharmacological proof of its biological function in tumor-bearing mice. Drug candidate <b>3</b> was superior to compound <b>7</b> in its ability to prevent tumor growth and metastasis. Compound <b>3</b> suppressed myeloid-derived suppressor cell (MDSC) accumulation in the spleens of tumor-bearing mice and decreased various serum inflammatory cytokines levels. Furthermore, compound <b>3</b> antagonized the nucleotide-binding oligomerization domain-like receptor 1 (NOD1) signaling pathway both in vitro and in vivo