Recent experimental studies have demonstrated that single molecules or a small number of self-assembled molecules can perform the basic functions of traditional electronic components, such as wires and diodes. In particular, molecular wires inserted into nanopores can be used as active elements for the fabrication of resonant tunneling diodes (RTDs), whose I/V characteristics reveal a Negative Differential Resistance (NDR) behavior (i.e., a negative slope in the I/V curve). Here, quantum-chemical calculations are used to describe on a qualitative basis the mechanism leading to NDR in polyphenylene-based molecular wires incorporating saturated spacers. This description is based on the characterization of the evolution of the wire electronic structure as a function of a static electric field applied along the molecular axis, which simulates the driving voltage between the two electrodes in the RTD devices. We illustrate that the main parameters controlling the NDR behavior can be modulated through molecular engineering of the wires.