The successful incorporation of molecules as active circuit elements relies on the ability to tune their electronic properties through chemical design. A synthetic strategy that has been used to manipulate and gate circuit conductance involves attaching a pendant substituent along the molecular conduction pathway. However, such a chemical gate has not yet been shown to significantly modify conductance. Here, we report a novel series of triarylmethylium and triangulenium carbocations gated by different substituents coupled to the delocalized conducting orbitals on the molecular backbone through a Fano resonance. By changing the pendant substituents to modulate the position of the Fano resonance and its coupling to the conducting orbitals, we can regulate the junction conductance by a remarkable factor of 450. This work thus provides a new design principle to enable effective chemical gating of single-molecule devices toward effective molecular transistors.