The vanilla game can be played in quite challenging ways; perma death, no bosses, no map, no portals or any combination of these.

And by doing the above you will find most random seeds will work fine and in no way will reduce the self imposed challenges.

If you have played the game through at least once (all current bosses) and have a good understanding of how things work then I would suggest a 'no bosses/no portals' run.