# Can Fascaplysins Be Considered Analogs of Indolo[2,3-a]pyrrolo[3,4-c]carbazoles? Comparison of Biosynthesis, Biological Activity and Therapeutic Potential

## TL;DR

This paper compares the biosynthesis and biological activity of three natural product families, finding that fascaplysins act through unique mechanisms and have potential as antibiotic leads.

## Contribution

The study presents the first comparative analysis of biosynthesis and biological activity of fascaplysins and related alkaloids, revealing distinct mechanisms and therapeutic potential.

## Key findings

- Fascaplysins induce metabolic stress rather than inhibit DNA topoisomerase I or protein kinases.
- Indolo[2,3-a]pyrrolo[3,4-c]carbazoles can be optimized into drug-like candidates despite initial pharmacokinetic limitations.
- Fascaplysin derivatives show promise as leads for new antibiotics after improving their pharmacokinetic properties.

## Abstract

For the first time, a comparative analysis has been conducted to elucidate the biosynthesis of three families of natural products—staurosporines/rebeccamycins, cladoniamides, and fascaplysins. Based on the available data, a well-founded hypothesis was formed that these metabolites arise through a shared biosynthetic pathway. A comparative evaluation of biological activity profiles and molecular mechanisms of action of the major representatives of these alkaloid families and their derivatives shows that, despite an apparent similarity between the activity spectra of indolo[2,3-a]pyrrolo[3,4-c]carbazoles and fascaplysins, they operate through different mechanisms. The biological effects of fascaplysin are driven primarily by the induction of metabolic stress rather than by the inhibition of DNA topoisomerase I or of a broad-spectrum protein kinases. The successful optimization of natural indolo[2,3-a]pyrrolo[3,4-c]carbazoles—compounds with initially poorer pharmacokinetic properties than those of fascaplysin—to drug-like candidates underscores the substantial pharmaceutical potential of the fascaplysin scaffold. Several existing fascaplysin derivatives, after the improvement of their pharmacokinetic characteristics, may serve as promising leads for the development of a new class of antibiotics.